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Pressure-sensitive renal juxtaglomerular cells release renin, which stimulates production of angiotensin and influences aldosterone production, both of which affect an increase of blood volume.Two slower-acting humoral mechanisms regulate blood volume and complement the control of systemic vascular resistance.Thus, vagal activity results in reduction in heart rate and in the contractile force of the myocardium (negative inotropy). Increased systemic vascular resistance is mediated concurrently through parallel connections between the NTS and the medullary pressor areas that project to the intermediolateral cells of the midthoracic cord. The main sympathetic outflow from these thoracic segments is via the greater splanchnic nerve to the celiac ganglion, the postganglionic nerves of which project to the capacitance vessels of the gut. The splanchnic capacitance veins act as a reservoir for as much as 20 percent of the total blood volume, and interruption of the splanchnic nerves results in severe postural hypotension. After a high-carbohydrate meal there is a marked hyperemia of the gut and compensatory peripheral vasoconstriction in the muscles and skin. It has also been noted that the mesenteric vascular bed is responsive to the orthostatic redistribution of blood volume but not to mental stress. The opposite response to the one described earlier, namely bradycardia and hypotension, results when vagal tone is enhanced and sympathetic tone reduced. This response can be triggered by baroreceptors, or it may arise from cerebral stimuli such as fear or sight of blood in susceptible individuals as well as from extreme pain, particularly arising in the viscera. Two slower-acting humoral mechanisms regulate blood volume and complement the control of systemic vascular resistance. Pressure-sensitive renal juxtaglomerular cells release renin, which stimulates production of angiotensin and influences aldosterone production, both of which affect an increase of blood volume.In addition to its presence in autonomic ganglia, nitric oxide has been found to have an important local role in maintaining vascular tone, mainly by way of attenuating the response to sympathetic stimulation.The extent to which this latter function is under neural control is not clear.
The microvilli increase the surface area available for exchange of materials between hepatocytes and plasma by as much as six times.18.9).Small, irregular microvilli project into this space from the basal surface of the hepatocytes (Fig.Like other members of the mononuclear phagocytotic system, Kupffer cells are derived from monocytes. The scanning electron microscope (SEM) and transmission electron microscope (TEM) clearly show that the Kupffer cells form part of the lining of the sinusoid. Previously, they had been described as lying on the luminal surface of the endothelial cells. This older histologic description was probably based on the fact that processes of the Kupffer cells occasionally overlap endothelial processes on the luminal side. Kupffer cells do not form junctions with neighboring endothelial cells. Processes of Kupffer cells often seem to span the sinusoidal lumen and may even partially occlude it. The presence of red cell fragments and iron in the form of ferritin in the cytoplasm of Kupffer cells suggests that they may be involved in the final breakdown of some damaged or senile red blood cells that reach the liver from the spleen. Some of the ferritin iron may be converted to hemosiderin granules and stored in the cells. This function is greatly increased after splenectomy when it is then essential for red blood cell disposal. Perisinusoidal Space (Space of Disse) The perisinusoidal space is the site of exchange of materials between blood and liver cells. The perisinusoidal space (space of Disse) lies between the basal surfaces of hepatocytes and the basal surfaces of endothelial cells and Kupffer cells that line the sinusoids. Small, irregular microvilli project into this space from the basal surface of the hepatocytes (Fig. 18.9). The microvilli increase the surface area available for exchange of materials between hepatocytes and plasma by as much as six times.One hepatic sinusoid (top) displays a stellate sinusoidal macrophage (Kupffer cell).The remainder of the sinusoid as well as the other sinusoid is lined by thin endothelial cell cytoplasm.Surrounding each sinusoid is the perisinusoidal space (space of Disse), which contains numerous hepatocyte microvilli.
It has also been shown, by the use of a sensitive radio-immunoassay, that the CSF of many patients contains high concentrations of MBP during acute exacerbations of MS and that these levels are lower or normal in slowly progressive MS and normal during remissions of the disease.The same diseases mentioned above as being associated with oligoclonal bands can also increase the IgG index.It has been shown that the gamma globulin proteins in the CSF of patients with MS are synthesized in the CNS (Tourtellotte and Booe) and that they migrate in agarose electrophoresis as abnormal discrete populations. These oligoclonal bands in the CSF (after comparing to monoclonal proteins that may be present in the serum) are detected in more than 90 percent of cases of MS in some populations, but in a lower proportion of patients in Asian countries. Furthermore, oligoclonal bands are not specific for MS; such bands also appear in the CSF of patients with disorders such as syphilis, Lyme, and subacute sclerosing panencephalitis. The presence of bands in a first attack of MS is predictive of a chronic relapsing course, according to Moulin and coworkers and others. Oligoclonal bands are usually reported as being present if there is more than 1 band; the meaning of a single band is not clear, and we have treated this result as a negative test. As will be pointed out, the conditions of necrotic myelopathy and Devic disease generally lack oligoclonal bands. Also, in approximately 40 percent of patients, the total protein content of the CSF is increased. The increase is slight, however, and a concentration of more than 100 mg/dL is so unusual that the possibility of another diagnosis should be entertained. Another diagnostic test sometimes used is measurement of IgG and the IgG index in the CSF. The latter refers to proportion of gamma globulin (mainly IgG) in reference to the total protein in CSF; a positive test is considered to be greater than 12 percent of the total protein. The same diseases mentioned above as being associated with oligoclonal bands can also increase the IgG index. It has also been shown, by the use of a sensitive radio-immunoassay, that the CSF of many patients contains high concentrations of MBP during acute exacerbations of MS and that these levels are lower or normal in slowly progressive MS and normal during remissions of the disease.Thus the assay is not particularly useful as a diagnostic test and probably simply reflects the destruction of central myelin.
% 5 03 × 10 es .mol −13 ° 0 002.× 10 moles Therefore,thediffusionof1.05× 10−17molesofK+ outofthecellrepresentsonlya0.002%changeintheintracellularK+ content: .012 .mol/L = 5 03 .× 10 mole ofK , ombs/mol Withacellvolumeof4.19× 10−12L(volume= 4πr3/3)andanintracellular[K+]of120mmol/L,thetotalintracellularK+ contentis 4 19 × 10 × .coul = 1 05.The dependence of the Vm on the conductance of the membrane to specific ions is the basis by which action potentials in excitable cells are generated ( Fig. 2.5). As noted previously, in all excitable cells, the CHAPTER 2 Homeostasis: Volume and Composition of Body Fluid Compartments membrane at rest is conductive predominantly to K+ , and thus Vm is near EK+. When an action potential is initiated, Na+-channels open and the membrane is now conductive predominantly to Na+ . As a result, Vm now approaches ENa+. The generation of action potentials is discussed in more detail in TheestablishmentoftheVmrequirestheseparationofchargeacrosstheplasmamembrane.However,thenumberofionsthatmustmoveacrossthemembraneisatinyfractionofthetotalnumberofionsinthecell.Forexample,considerasphericalcellwithadiameterof20µmandaVmof−80mV.Furthermore,assumethatthisVmof−80mVistheresultofthediffusionofK+ outofthecellandthattheintracellular[K+]is120mmol/L.TheamountofK+ thatwouldhavetodiffuseoutofthecelltoestablishtheVmof−80mVisthencalculatedasfollows. Firstthechargeseparationacrossthemembraneneedstobecalculated.Thisisdonewiththeknowledgethattheplasmamembranebehaveselectricallylikeacapacitor,thecapacitance(C)ofwhichisapproximately1µF/cm2,and whereQ= chargeandisexpressedinunitsofcoulombs.Ifthesurfaceareaofthecellis4πr2or1.26× 10−5cm2,thecapacitanceofthecelliscalculatedasfollows: 1× 10 F/cm × . × 10 cm = . × 10 126 126 F. Thusthechargeseparationacrossthemembraneiscalculatedasfollows: 1 01× 10−12 coulombs. Because1moleofK+ contains96,480coulombs,theamountofK+ thathadtodiffuseacrossthemembranetoestablishtheVmof−80mViscalculatedasfollows: . coul = 1 05. × 10 mole ofK , ombs/mol Withacellvolumeof4.19× 10−12L(volume= 4πr3/3)andanintracellular[K+]of120mmol/L,thetotalintracellularK+ contentis 4 19 × 10 × . mol/L = 5 03 . 012 . × 10 moles Therefore,thediffusionof1.05× 10−17molesofK+ outofthecellrepresentsonlya0.002%changeintheintracellularK+ content: . mol −13 ° 0 002. % 5 03 × 10 es .Regulation of Cell Volume As already noted, changes in cell volume can lead to cell damage and death.Cells have developed mechanisms to regulate their volume.Most cells are highly permeable by water because of the presence of aquaporins in their plasma membranes.
Atypical antipsychotics (e.g., clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) are thought to be associated with a lower risk of TD in comparison to traditional antipsychotics, although this remains to be established in controlled studies.The abrupt onset of severe spasms may occasionally be confused with a seizure; however, there is no loss of consciousness, automatisms, or postictal features typical of epilepsy. The acute onset of chorea, stereotypic behavior, and tics may also be seen, particularly following exposure to CNS stimulants such as methylphenidate, cocaine, or amphetamines. Akathisia is the commonest reaction in this category. It consists of motor restlessness with a need to move that is alleviated by movement. Therapy consists of removing the offending agent. When this is not possible, symptoms may be ameliorated with benzodiazepines, anticholinergics, beta blockers, or dopamine agonists. These disorders develop months to years after initiation of neuroleptic treatment. Tardive dyskinesia (TD) is most common and typically presents with choreiform movements involving the mouth, lips, and tongue. In severe cases, the trunk, limbs, and respiratory muscles may also be affected. In approximately one-third of patients, TD remits within 3 months of stopping the drug, and most patients gradually improve over the course of several years. Abnormal movements may also develop or worsen after stopping the offending agent. The movements are often mild and more upsetting to the family than to the patient, but they can be severe and disabling, particularly in the context of an underlying psychiatric disorder. Atypical antipsychotics (e.g., clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) are thought to be associated with a lower risk of TD in comparison to traditional antipsychotics, although this remains to be established in controlled studies.Chronic use is associated with increased risk, and specifically, the U.S. Food and Drug Administration has warned that use of metoclopramide for more than 12 weeks increases the risk of TD.
282-1).The ductus arteriosus is a vessel leading from the bifurcation of the pulmonary artery to the aorta just distal to the left subclavian artery (Fig.Iron repletion in decompensated iron-depleted erythrocytosis reduces iron-deficiency symptoms, but must be done gradually to avoid an excessive rise in hematocrit and resulting hyperviscosity.Iron-deficiency symptoms are usually indistinguishable from those of hyperviscosity; progressive symptoms after recurrent phlebotomy are usually due to iron depletion with hypochromic microcytosis. Iron depletion results in a larger number of smaller (microcytic) hypochromic red cells that are less capable of carrying oxygen and less deformable in the microcirculation; with more of them relative to plasma volume, viscosity is greater than for an equivalent hematocrit with fewer, larger, iron-replete, deformable cells. As such, iron-depleted erythrocytosis results in increasing symptoms due to decreased oxygen delivery to the tissues. Hemostasis is abnormal in cyanotic CHD, due, in part, to the increased blood volume and engorged capillaries, abnormalities in platelet function, and sensitivity to aspirin or nonsteroidal anti-inflammatory agents, as well as abnormalities of the extrinsic and intrinsic coagulation system. Oral contraceptives are often contraindicated for cyanotic women because of the enhanced risk of vascular thrombosis. Symptoms of hyperviscosity can be produced in any cyanotic patient with erythrocytosis if dehydration reduces plasma volume. Phlebotomy for symptoms of hyperviscosity not due to dehydration or iron deficiency is a simple outpatient removal of 500 mL of blood over 45 min with isovolumetric replacement with isotonic saline. Acute phlebotomy without volume replacement is contraindicated. Iron repletion in decompensated iron-depleted erythrocytosis reduces iron-deficiency symptoms, but must be done gradually to avoid an excessive rise in hematocrit and resulting hyperviscosity. The ductus arteriosus is a vessel leading from the bifurcation of the pulmonary artery to the aorta just distal to the left subclavian artery (Fig. 282-1).The flow across the ductus is determined by the pressure and resistance relationships between the systemic and pulmonary circulations and by the cross-sectional area and length of the ductus.
The neoadjuvant setting is also an ideal time to evaluate the efficacy of novel treatments because the effect on the tumor can be directly assessed.Such approaches produce long-term disease-free survival in about 30–50% of patients.These patients should be managed in multimodality clinics to coordinate surgery, radiation therapy, and systemic chemotherapy.It is a sad fact that choices are often influenced by aggressive marketing of new very expensive agents that have not been shown to be superior to other generic agents. Platinum-based agents have become far more widely used in both the adjuvant and advanced disease settings for some breast cancers, particularly those of the “triple-negative” subtype. high-dose chemotheraPy including autologous Bone marrow transPlantation Autologous bone marrow transplantation combined with high doses of single agents can produce objective responses even in heavily pretreated patients. However, such responses are rarely durable and do not alter the clinical course for most patients with advanced metastatic disease. Between 10 and 25% of patients present with so-called locally advanced, or stage III, breast cancer at diagnosis. Many of these cancers are technically operable, whereas others, particularly cancers with chest wall involvement, inflammatory breast cancers, or cancers with large matted axillary lymph nodes, cannot be managed with surgery initially. Although no randomized trials have shown any survival benefit for neoadjuvant regimens as compared to adjuvant therapy, this approach has gained widespread use. More than 90% of patients with locally advanced breast cancer show a partial or better response to multidrug chemotherapy regimens that include an anthracycline. Early administration of this treatment reduces the bulk of the disease and frequently makes the patient a suitable candidate for salvage surgery and/or radiation therapy. These patients should be managed in multimodality clinics to coordinate surgery, radiation therapy, and systemic chemotherapy. Such approaches produce long-term disease-free survival in about 30–50% of patients. The neoadjuvant setting is also an ideal time to evaluate the efficacy of novel treatments because the effect on the tumor can be directly assessed.When adjuvant tamoxifen or an aromatase inhibitor is administered to these patients, the rate of development of contralateral breast cancers is reduced.In other tissues of the body, tamoxifen has estrogen-like effects that are beneficial, including preservation of bone mineral density and long-term lowering of cholesterol.
• Tests of platelet function.Counts outside this range must be confirmed by a visual inspection of a peripheral blood smear.The reference range is 150,000 to 450,000/µL.This is obtained on anti-coagulated blood using an electronic particle counter.Platelet count.It follows that abnormalities in any of these components can lead to clinically significant bleeding. A review of the laboratory tests used in the evaluation of patients with a suspected bleeding disorder, along with the principles involved, is presented next, followed by consideration of specific disorders of coagulation. We finish with a discussion of a few clinically important complications of blood product transfusion. The most important tests for investigation of suspected coagulopathies include the following: Prothrombin time (PT). This test assesses the extrinsic and common coagulation pathways. It measures the time (in seconds) needed for plasma to clot after addition of tissue thromboplastin (e.g., brain extract) and Ca2+ ions. A prolonged PT can result from a deficiency of factor V, VII, or X; prothrombin; or fibrinogen or the presence of an acquired inhibitor (typically an antibody) that interferes with the extrinsic pathway. Partial thromboplastin time (PTT). This test assesses the intrinsic and common coagulation pathways. It measures the time (in seconds) needed for the plasma to clot after the addition of kaolin, cephalin, and Ca2+ . Kaolin activates the contact-dependent factor XII and cephalin substitutes for platelet phospholipids. Prolongation of PTT can be caused by a deficiency of factor V, VIII, IX, X, XI, or XII; prothrombin; or fibrinogen or the presence of an acquired inhibitor that interferes with the intrinsic pathway. Platelet count. This is obtained on anti-coagulated blood using an electronic particle counter. The reference range is 150,000 to 450,000/µL. Counts outside this range must be confirmed by a visual inspection of a peripheral blood smear. • Tests of platelet function.Aggregation tests that measure the response of platelets to certain agonists and qualitative and quantitative tests of von Willebrand factor (vWF) (which you will recall is required for platelet adherence to subvascular collagen) are both commonly used in clinical practice.
Available @ StudentConsult.com Abnormal Head Size, Shape, and Toxoplasma gondii Heterophil-negative mononucleosis Hydrocephalus, abnormal spinal fluid, intracranial Exposure to cats or raw meat or calcifications, chorioretinitis, jaundice, hepatosplenomegaly, immunosuppression fever High-risk exposure at 10–24 wk gestation Many infants asymptomatic at birth Treatment: pyrimethamine plus sulfadiazine Rubella virus Unimmunized seronegative mother; fever ± rash Detectable defects with infection: by 8 wk, 85% 9–12 wk, 50% 13–20 wk, 16% Virus may be present in infant’s throat for 1 yr Prevention: vaccine Intrauterine growth restriction, microcephaly, microphthalmia, cataracts, glaucoma, “salt and pepper” chorioretinitis, hepatosplenomegaly, jaundice, PDA, deafness, blueberry muffin rash, anemia, thrombocytopenia, leukopenia, metaphyseal lucencies, B-cell and T-cell deficiency Infant may be asymptomatic at birth CMV Sexually transmitted disease: primary genital infection may be asymptomatic Heterophil-negative mononucleosis; infant may have viruria for 1–6 yr Sepsis, intrauterine growth restriction, chorioretinitis, microcephaly, periventricular calcifications, blueberry muffin rash, anemia, thrombocytopenia, neutropenia, hepatosplenomegaly, jaundice, deafness, pneumonia Many asymptomatic at birth Prevention: CMV-negative blood products Possible treatment: ganciclovir (syphilis) asymptomatic: painless “hidden” chancre Penicillin, not erythromycin, prevents fetal infection Presentation at birth as nonimmune hydrops, prematurity, anemia, neutropenia, thrombocytopenia, pneumonia, hepatosplenomegaly Late neonatal as snuffles (rhinitis), rash, hepatosplenomegaly, condylomata lata, metaphysitis, cerebrospinal fluid pleocytosis, keratitis, periosteal new bone, lymphocytosis, hepatitis Late onset: teeth, eye, bone, skin, central nervous system, ear Treatment: penicillin Parvovirus Etiology of fifth disease; fever, rash, arthralgia in Nonimmune hydrops, fetal anemia adults Treatment: in utero transfusion Trypanosoma cruzi Central South American native, immigrant, travel Failure to thrive, heart failure, achalasia (Chagas disease) Chronic disease in mother Treatment: nifurtimox AZT, Zidovudine (azidothymidine); BCG, bacille Calmette-Guerin; CMV, cytomegalovirus; HBIG, hepatitis B immune globulin; INH, isoniazid; PDA, patent ductus arteriosus; PPD, purified protein derivative; TB, tuberculosis; VZIG, varicella-zoster immune globulin.Acquired in utero during early gestation, rubella can cause severe neonatal consequences.The occurrence of congenital defects approaches 85% if infection is acquired during the first 4 weeks of gestation; close to 40% spontaneously abort or are stillborn.If infection occurs during weeks 13 to 16, 35% of infants can have abnormalities.
When more than one substance is judged to play a significant role in the development of anxiety symptoms, each should be listed sep- arately (e.g., F15.280 severe methylphenidate use disorder with methylphenidate—induced anxiety disorder, with onset during intoxication; F19.980 salbutamol-induced anxiety dis- order, with onset after medication use).The diagnostic code is selected from the table included in the criteria set, Which is based on the drug class and presence or absence of a comorbid substance use disorder. For substances that do not fit into any of the classes (e.g., salbutamol), the code for ”other substance” should be used; and in cases in which a substance is judged to be an etiological factor but the specific class of substance is unknown, the category “unknown substance” should be used. When recording the name of the disorder, the comorbid substance use disorder (if any) is listed first, followed by the word ”with,” followed by the name of the substance-induced anxiety disorder, followed by the specification of onset (i.e., onset during intoxication, onset during withdrawal, with onset during medication use). For example, in the case of anxiety symptoms occurring during withdrawal in a man with a severe lorazepam use dis- order, the diagnosis is F13.280 severe lorazepam use disorder with lorazepam-induced anxiety disorder, with onset during withdrawal. A separate diagnosis of the comorbid se- vere lorazepam use disorder is not given. If the substance-induced anxiety disorder occurs without a comorbid substance use disorder (e.g., after a one-time heavy use of the substance), no accompanying substance use disorder is noted (e.g., F16.980 psilocybin—induced anxi- ety disorder, with onset during intoxication). When more than one substance is judged to play a significant role in the development of anxiety symptoms, each should be listed sep- arately (e.g., F15.280 severe methylphenidate use disorder with methylphenidate—induced anxiety disorder, with onset during intoxication; F19.980 salbutamol-induced anxiety dis- order, with onset after medication use).The panic or anxiety symp- after exposure to a medication, and the substances or medications must be capable of pro— ducing the symptoms (Criterion B2).
Laudanosine is slowly metabolized by the liver and has a longer elimination half-life (ie, 150 minutes).The main breakdown products are laudanosine and a related quaternary acid, neither of which possesses neuromuscular blocking properties.In addition to hepatic metabolism, atracurium is inactivated by a form of spontaneous breakdown known as Hofmann elimination.Drugs that are excreted by the kidney typically have longer half-lives, leading to longer durations of action (>35 minutes). Drugs eliminated by the liver tend to have shorter half-lives and durations of action (Table 27–1). All steroidal muscle relaxants are metabolized to their 3-hydroxy, 17-hydroxy, or 3,17-dihydroxy products in the liver. The 3-hydroxy metabolites are usually 40–80% as potent as the parent drug. Under normal circumstances, metabolites are not formed in sufficient quantities to produce a significant degree of FIGURE 27–4 Structures of steroid neuromuscular blocking drugs (steroid nucleus in color). These agents are all nondepolarizing muscle relaxants. neuromuscular blockade during or after anesthesia. However, if the parent compound is administered for several days in the ICU setting, the 3-hydroxy metabolite may accumulate and cause prolonged paralysis because it has a longer half-life than the parent compound. The remaining metabolites possess minimal neuromuscular blocking properties. The intermediate-acting steroid muscle relaxants (eg, vecuronium and rocuronium) tend to be more dependent on biliary excretion or hepatic metabolism for their elimination. These muscle relaxants are more commonly used clinically than the long-acting steroid-based drugs (eg, pancuronium). The duration of action of these relaxants may be prolonged significantly in patients with impaired liver function. Atracurium (Figure 27–3) is an intermediate-acting isoquinoline nondepolarizing muscle relaxant that is no longer in widespread clinical use. In addition to hepatic metabolism, atracurium is inactivated by a form of spontaneous breakdown known as Hofmann elimination. The main breakdown products are laudanosine and a related quaternary acid, neither of which possesses neuromuscular blocking properties. Laudanosine is slowly metabolized by the liver and has a longer elimination half-life (ie, 150 minutes).During surgical anesthesia, blood levels of laudanosine typically range from 0.2 to 1 mcg/mL; however, with prolonged infusions of atracurium in the ICU, laudanosine blood levels may exceed 5 mcg/mL.Atracurium has several stereoisomers, and the potent isomer cisatracurium has become one of the most common muscle relaxants in use today.
These procedures make it possible to distinguish among the several types of vascular malformations, arteriovenous fistulas, and vascular tumors, such as hemangioblastomas, and to localize them accurately to the spinal cord, epidural or subdural space, or vertebral bodies. This subject is discussed further on. Vascular Malformations and Dural Fistulas of the Spinal Cord These lesions cause both ischemic and hemorrhagic lesions. Some are true arteriovenous malformations (AVMs), implying a congenital connection between the two sides of the circulation and others are more limited fistulas in the dura, probably mostly acquired for various reasons. The distinction is in the size of the nidus of communication between an artery and a vein and the size and location of feeding and draining vessels. The classification of spinal AVMs is confusing, in part because the enlarged draining veins by which the lesions were formerly identified are probably secondary features. A more useful categorization reflects the appearance and location of the malformation: (1) arteriovenous malformations that are strictly intramedullary or that also involve the meninges and surrounding structures, such as the vertebral bodies, to a limited extent; (2) a variety of intradural perimedullary fistulas that lie on the pial and subpial surface of the cord (these probably conform most closely to the lesion described by Foix and Alajouanine discussed in the earlier section “Foix-Alajouanine Myelopathy”); and (3) dural fistulas.Once recognized, treatment of a spinal cord malformation of any type may be an urgent matter, especially in cases with rapid clinical deterioration and impending paralysis.Dural arteriovenous fistula The entity is addressed first because it has emerged as the most common type, at least in our practices.
267-2D).In some patients with AR or with combined AS and AR, the carotid arterial pulse may be bisferiens, i.e., with two systolic waves separated by a trough (see Fig.This systolic thrill and the accompanying murmur do not necessarily signify the coexistence of AS.A booming “pistol-shot” sound can be heard over the femoral arteries (Traube’s sign), and a to-and-fro murmur (Duroziez’s sign) is audible if the femoral artery is lightly compressed with a stethoscope. The arterial pulse pressure is widened as a result of both systolic hypertension and a lowering of the diastolic pressure. The measurement of arterial diastolic pressure with a sphygmomanometer may be complicated by the fact that systolic sounds are frequently heard with the cuff completely deflated. However, the level of cuff pressure at the time of muffling of the Korotkoff sounds (phase IV) generally corresponds fairly closely to the true intraarterial diastolic pressure. As the disease progresses and the LV end-diastolic pressure rises, the arterial diastolic pressure may actually rise as well, because the aortic diastolic pressure cannot fall below the LV end-diastolic pressure. For the same reason, acute severe AR may also be accompanied by only a slight widening of the pulse pressure. Such patients are invariably tachycardic as the heart rate increases in an attempt to preserve the CO. Palpation In patients with chronic severe AR, the LV impulse is heaving and displaced laterally and inferiorly. The systolic expansion and diastolic retraction of the apex are prominent. A diastolic thrill may be palpable along the left sternal border in thin-chested individuals, and a prominent systolic thrill may be palpable in the suprasternal notch and transmitted upward along the carotid arteries. This systolic thrill and the accompanying murmur do not necessarily signify the coexistence of AS. In some patients with AR or with combined AS and AR, the carotid arterial pulse may be bisferiens, i.e., with two systolic waves separated by a trough (see Fig. 267-2D).A systolic ejection sound is audible in patients with BAV disease, and occasionally an S4 also may be heard.The murmur of chronic AR is typically a high-pitched, blowing, decrescendo diastolic murmur, heard best in the third intercostal space along the left sternal border (see Fig.267-5B).
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.Treatment may be required for only a limited period of time and the possible increased risk for breast cancer avoided.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. If the main indication for therapy is hot flushes and sleep disturbances, therapy with the lowest dose of estrogen required for symptomatic relief is recommended. 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.The role of estrogens in the prevention and treatment of osteoporosis has been carefully studied (see Chapter 42).The amount of bone present in the body is maximal in the young active adult in the third decade of life and begins to decline more rapidly in middle age in both men and women.
They may offer excuses for the difficulties—“I lost my glasses,” “The light is dim”—or may only evince indifference to loss of sight.These patients act as though they could see, and in attempting to walk, collide with objects, even to the point of injury.The main characteristic of this disorder is the denial of blindness by a patient who obviously cannot see.16).The eyes are still able to move through a full range and, if there is macular sparing as there usually is with vascular lesions, optokinetic nystagmus can be elicited. Visual imagination and visual imagery in dreams are preserved. With rare exceptions, no cortical potentials can be evoked in the occipital lobes by light flashes or pattern changes (visual evoked response), and the alpha rhythm is lost in the electroencephalogram (EEG; see Chap. 2). Less-complete bilateral lesions leave the patient with varying degrees of visual perception. There may also be visual hallucinations of either elementary or complex types. The mode of recovery from cortical blindness has been studied carefully by Gloning and colleagues, who describe a regular progression from cortical blindness through visual agnosia and partially impaired perceptual function to recovery. Even with recovery, the patient may complain of visual fatigue (asthenopia) and difficulties in fixation and fusion. The usual cause of cortical blindness is occlusion of the posterior cerebral arteries (most often embolic) or the equivalent, occlusion of the distal basilar artery. The above-mentioned macular sparing may leave the patient with an island of barely serviceable central vision. The infarct may also involve the mediotemporal regions or thalami, which share the posterior cerebral artery supply, with a resulting Korsakoff amnesic defect and a variety of other neurologic deficits referable to the high midbrain and diencephalon (drowsiness, akinetic mutism as described in Chap. 16). The main characteristic of this disorder is the denial of blindness by a patient who obviously cannot see. These patients act as though they could see, and in attempting to walk, collide with objects, even to the point of injury. They may offer excuses for the difficulties—“I lost my glasses,” “The light is dim”—or may only evince indifference to loss of sight.Rarely, the opposite condition arises: a patient is able to see small objects but claims to be blind.This individual walks about avoiding obstacles, picks up crumbs or pills from the table, and catches a small ball thrown from a distance.This simulates the condition of hysterical blindness (see further on).These may present as distortions of form, size, movement, or color.
Adverse drug reactions were suspected by physicians in 1.2% of patients, but there were no serious adverse reactions (36).After use in three cycles, 93% of women reported a decrease in or cessation of symptoms, and 94% of patients reported good or very good tolerance to this botanical.A multicenter noninterventional trial examined the experience and tolerance of chasteberry in 1,634 patients.One study looked at essential fatty Table 13.7 Omega-3 Content of Foodsa a For general health, individuals should try to consume 7–10 g of omega-3 fatty acids weekly. Data from United States Department of Agriculture. USDA national nutrient database. Beltsville, MD: USDA; 2004. Available online at http://www.nal.usda.gov/fnic/foodcomp/search acids (EFA) and PMS and showed no effect. There are some positive studies looking at the effectiveness of omega-3 fatty acids in treating mild depression with fish oils. This may be a reasonable approach to try if one of the patient’s primary symptoms is mood depression (3 g, divided with meals) (33). Side effects are rare, but occasionally patients will experience nausea, diarrhea, belching, or an unpleasant taste in the mouth. Omega-3 fatty acids have an anticoagulant effect and are relatively high in calories. Chasteberry Chasteberry (Vitex agnus-castus) is a botanical with a long history of use for “menstrual disorders.” Many small studies have shown promising results, and one larger study examined the effectiveness of chasteberry on PMDD (34,35). In this randomized controlled trial, the active arm received 20 mg of chasteberry daily. Compared with placebo, the patients receiving chasteberry had a significant improvement in the combined symptom score (35). A multicenter noninterventional trial examined the experience and tolerance of chasteberry in 1,634 patients. After use in three cycles, 93% of women reported a decrease in or cessation of symptoms, and 94% of patients reported good or very good tolerance to this botanical. Adverse drug reactions were suspected by physicians in 1.2% of patients, but there were no serious adverse reactions (36).In both arms, there were significantly improved symptoms.Two of the three randomized controlled trials evaluating chasteberry for PMS showed some benefit on symptoms such as irritability, mood swings, anger, breast tenderness, and headaches.In the study with no benefit, the placebo arm was a soy-based product, which may reduce symptoms of PMS.
The effects of vascular occlusion range from inconsequential to tissue necrosis leading to organ dysfunction and sometimes death.4.18 Remotekidneyinfarct,nowreplacedbyalargefibroticscar.Fig.Inthesecasestheinfarctisconvertedintoanabscess,withacorrespondinglygreaterinflammatoryresponseandhealingbyorganizationandfibrosis(Chapter3).White infarcts occurwitharterialocclusionsinsolidorganswithend-arterialcirculations(e.g.,heart,spleen,andkidney),andwheretissuedensitylimitstheseepageofbloodfromadjoiningpatentvascularbeds( Fig.4.17B ).Infarctstendtobewedge-shaped,withtheoccludedvesselattheapexandtheorganperipheryformingthebase( Fig.4.17 );whenthebaseisaserosalsurface,thereisoftenanoverlyingfibrinousexudate.Lateralmarginsmaybeirregular,reflectingflowfromadjacentvessels.Themarginsofacuteinfarctstypicallyareindistinctandslightlyhemorrhagic;withtime,theedgesbecomebetterdefinedbyanarrowrimofhyperemiaattributabletoinflammation. Fig.4.17B ).Bycomparison,hemorrhagicinfarctsaretheruleinthelungandotherspongyorgans( Fig.4.17A ).Extravasatedredcellsinhemorrhagicinfarctsarephagocytosedbymacrophages,andthehemeironisconvertedtointracellularhemosiderin.Smallamountsdonotimpartanyappreciablecolortothetissue,butextensivehemorrhagesleaveafirm,brownresidue. Inmosttissues,themainhistologicfindingassociatedwithinfarctsisischemic coagulative necrosis (Chapter2).Aninflammatoryresponsebeginstodevelopalongthemarginsofinfarctswithinafewhoursandusuallyiswelldefinedwithin1to2days.Eventually,inflammationisfollowedbyrepair,beginninginthepreservedmargins(Chapter3).Insometissues,parenchymalregenerationcanoccurattheperipheryoftheinfarct,wheretheunderlyingstromalarchitecturehasbeenspared.Mostinfarcts,however,areultimatelyreplacedbyscar( Fig.4.18 ).Thebrainisanexceptiontothesegeneralizations;ischemictissueinjuryinthecentralnervoussystemresultsinliquefactive necrosis (Chapter2). Septic infarctis occurwheninfectedcardiacvalvevegetationsembolize,orwhenmicrobesseednecrotictissue. Inthesecasestheinfarctisconvertedintoanabscess,withacorrespondinglygreaterinflammatoryresponseandhealingbyorganizationandfibrosis(Chapter3). Fig. 4.18 Remotekidneyinfarct,nowreplacedbyalargefibroticscar. The effects of vascular occlusion range from inconsequential to tissue necrosis leading to organ dysfunction and sometimes death.The presence or absence of an alternative blood supply is the most important factor in determining whether occlusion of an individual vessel causes damage.The dual supply of the lung by the pulmonary and bronchial arteries means that obstruction of the pulmonary arterioles does not cause lung infarction unless the bronchial circulation also is compromised.
The neuroma can be identified by the presence of a Tinel’s sign.As mentioned earlier, the surgeon should resect the nerve stump as far proximally in the wound as possible to avoid the nerve stump healing in the cutaneous scar to minimize this risk.For the patient who develops a painful neuroma, nonsurgi-cal treatments are initiated first.Scaphoid nonunions can be quite challenging to repair, and immobilization at the time of injury in a thumb spica splint is essentially always warranted.39StiffnessThe desired outcome of any hand injury is a painless, mobile, functional hand. Multiple factors can contribute to decreased mobility, including complex injuries of soft tissue and bone, noncompliance of the patient with postoperative therapy, and inappropriate splinting. The surgeon performing the initial eval-uation can greatly impact this last factor. The goal of splinting is to keep the collateral ligaments on tension (MPs at 90°, IP joints straight). For severe cases of stiffness, mobilization sur-geries such as tenolysis and capsulotomies can be performed, but these rarely produce normal range of motion.40 Prevention of joint contractures with appropriate splinting and early, pro-tected mobilization is the best option to maximize mobility at the end of healing. Healing of an injured or diseased structure in the hand is not the endpoint of treatment; the goal of any inter-vention must be to obtain structure healing, relief of pain, and maximization of function.NeuromaAny lacerated nerve will form a neuroma. A neuroma consists of a ball of scar and axon sprouts at the end of the injured nerve.41 In unfavorable circumstances, this neuroma can become painful. The SRN is particularly notorious for this problem. By provid-ing proximal axon sprouts a target, nerve repair is an excellent preventive technique. In some circumstances, such as injuries requiring amputation, this is not possible. As mentioned earlier, the surgeon should resect the nerve stump as far proximally in the wound as possible to avoid the nerve stump healing in the cutaneous scar to minimize this risk.For the patient who develops a painful neuroma, nonsurgi-cal treatments are initiated first. The neuroma can be identified by the presence of a Tinel’s sign.Corticosteroid injection to the neuroma has also proven useful in some hands.When these techniques fail, surgery is contemplated.The neuroma can be resected, but a new one will form to replace it.
lymphopenia Abnormally low levels of lymphocytes in the blood.lymphoid tissue inducer (LTi) cells Cells of the blood lineage, which arise in the fetal liver and are carried in the blood to sites where they will form lymph nodes and other peripheral lymphoid organs.lymphoid tissue Tissue composed of large numbers of lymphocytes.lymph nodes A type of peripheral lymphoid organ present in many locations throughout the body where lymphatic vessels converge. lymphatic system The system of lymph-carrying vessels and peripheral lymphoid tissues through which extracellular ﬂuid from tissues passes before it is returned to the blood via the thoracic duct. lymphatic vessels, lymphatics Thin-walled vessels that carry lymph. lymphoblast A lymphocyte that has enlarged after activation and has increased its rate of RNA and protein synthesis, but is not yet fully differentiated. lymphocyte A class of white blood cells that bear variable cell-surface receptors for antigen and are responsible for adaptive immune responses. There are two main types—B lymphocytes (B cells) and T lymphocytes (T cells)—which mediate humoral and cell-mediated immunity, respectively. On antigen recognition, a lymphocyte enlarges to form a lymphoblast and then proliferates and differentiates into an antigen-specific effector cell. lymphocyte receptor repertoire All the highly variable antigen receptors carried by B and T lymphocytes. lymphoid Describes tissues composed mainly of lymphocytes. lymphoid organs Organized tissues characterized by very large numbers of lymphocytes interacting with a nonlymphoid stroma. The central, or primary, lymphoid organs, where lymphocytes are generated, are the thymus and bone marrow. The main peripheral, or secondary, lymphoid organs, in which adaptive immune responses are initiated, are the lymph nodes, spleen, and mucosa-associated lymphoid organs such as tonsils and Peyer’s patches. lymphoid tissue Tissue composed of large numbers of lymphocytes. lymphoid tissue inducer (LTi) cells Cells of the blood lineage, which arise in the fetal liver and are carried in the blood to sites where they will form lymph nodes and other peripheral lymphoid organs. lymphopenia Abnormally low levels of lymphocytes in the blood.lymphotoxins (LTs) Cytokines of the tumor necrosis factor (TNF) family that are directly cytotoxic for some cells.They occur as trimers of LT-α chains (LT-α3) and heterotrimers of LT-α and LT-β chains (LT-α2:β1).
As for an N-terminal ER signal sequence, the SRP binds to an internal signal sequence by recognizing its hydrophobic α-helical features.In the other two cases, the signal sequence is internal, rather than at the N-terminal end of the protein.To release the signal sequence into the membrane, the translocator opens laterally along the seam (see Figures 12–35 and 12–39). The translocator is therefore gated in two directions: it opens to form a pore across the membrane to let the hydrophilic portions of proteins cross the lipid bilayer, and it opens laterally within the membrane to let hydrophobic portions of proteins partition into the lipid bilayer. Lateral gating of the pore is an essential step during the integration of transmembrane proteins. The integration of membrane proteins requires that some parts of the polypeptide chain be translocated across the lipid bilayer whereas others are not. Despite this additional complexity, all modes of insertion of membrane proteins are simply variants of the sequence of events just described for transferring a soluble protein into the lumen of the ER. We begin by describing the three ways in which single-pass transmembrane proteins (see Figure 10–17) become inserted into the ER membrane. In the simplest case, an N-terminal signal sequence initiates translocation, just as for a soluble protein, but an additional hydrophobic segment in the polypeptide chain stops the transfer process before the entire polypeptide chain is trans-located. This stop-transfer signal anchors the protein in the membrane after the ER signal sequence (the start-transfer signal) has been cleaved off and released from the translocator (Figure 12–42). The lateral gating mechanism transfers the stop-transfer sequence into the bilayer, where it remains as a single α-helical membrane-spanning segment, with the N-terminus of the protein on the lumenal side of the membrane and the C-terminus on the cytosolic side. In the other two cases, the signal sequence is internal, rather than at the N-terminal end of the protein. As for an N-terminal ER signal sequence, the SRP binds to an internal signal sequence by recognizing its hydrophobic α-helical features.After release from the translocator, the internal start-transfer sequence remains in the lipid bilayer as a single membrane-spanning α helix.
Developed in the 1990s, DNA microarrays are glass microscope slides that contain hundreds of thousands of DNA fragments, each of which serves as a probe for the mRNA produced by a specific gene.The first tool that allowed investigators to analyze simultaneously the thousands of different RNAs produced by cells or tissues was the DNA microarray.The first round of synthesis is the reverse transcription of the RNA into DNA using one of the primers. Next, a series of heating and cooling cycles allows the amplification of that DNA strand by PCR (see Figure 8–36). The quantitative part of this method relies on a direct relationship between the rate at which the PCR product is generated and the original concentration of the mRNA species of interest. By adding chemical dyes to the PCR that fluoresce only when bound to double-stranded DNA, a simple fluorescence measurement can be used to track the progress of the reaction and thereby accurately deduce the starting concentration of the mRNA that is amplified. Although it seems complicated, this quantitative RT-PCR technique is relatively fast and simple to perform in the laboratory; it is currently the method of choice for accurately quantifying mRNA levels from any given gene. Analysis of mRNAs by Microarray or RNA-seq Provides a Snapshot of Gene Expression As discussed in Chapter 7, a cell expresses only a subset of the many thousands of genes available in its genome; moreover, this subset differs from one cell type to another or, in the same cell, from one environment to the next. One way to determine which genes are being expressed by a population of cells or a tissue is to analyze which mRNAs are being produced. The first tool that allowed investigators to analyze simultaneously the thousands of different RNAs produced by cells or tissues was the DNA microarray. Developed in the 1990s, DNA microarrays are glass microscope slides that contain hundreds of thousands of DNA fragments, each of which serves as a probe for the mRNA produced by a specific gene.To do the analysis, mRNAs are extracted from cells or tissues and converted to cDNAs (see Figure 8–31).The cDNAs are fluorescently labeled and allowed to hybridize to the fragments bound to the microarray.An automated fluorescence microscope then determines which mRNAs were present in the original sample based on the array positions to which the cDNAs are bound (Figure 8–64).
)ComplicationsThe technical complication rate for pancreas transplants is higher than for any other solid organ transplant.New York, NY: Springer, 2004.(Reproduced from Gruessner RWG, Sutherland DER: Transplantation of the Pancreas.Whole-organ transplant with systemic vein and enteric exocrine drainage.The stapled technique requires that a circular cut-ting stapler be inserted through the open distal end of the donor duodenum, which is subsequently closed. Bladder drainage has two main advantages. First, rejection of the exocrine pancreas precedes rejection of the endocrine pancreas by 5 to 7 days. Amylase levels are measured routinely in the recipient’s urine. With bladder drainage, antirejection treatment can successfully be implemented when the recipient is still normoglycemic and only hypoamylasuric. In the absence of hyperglycemia, more than 90% of pancreas rejection episodes are reversible. Second, bladder drainage avoids the bacterial contamination that occurs with enteric drainage. If an anastomotic leak occurs, it is easier to treat because the infection usually remains localized to the right lower quadrant.Enteric drainage is more physiologic and has advantages as well. The antimesenteric side of the donor’s duodenum is anastomosed to the antimesenteric portion of the recipient’s jejunum in a side-to-side fashion. The enteric anastomosis can also involve a defunctionalized Roux-en-Y loop, which mini-mizes the potential complications if an enteric leak occurs.98 Currently, in the United States, more than 80% of all pancreas transplants are performed with enteric drainage for the exocrine pancreatic secretions, and more than 90% employ systemic venous drainage.95Brunicardi_Ch11_p0355-p0396.indd 37601/03/19 6:54 PM 377TRANSPLANTATIONCHAPTER 11Figure 11-13. Whole-organ transplant with systemic vein and enteric exocrine drainage. (Reproduced from Gruessner RWG, Sutherland DER: Transplantation of the Pancreas. New York, NY: Springer, 2004. )ComplicationsThe technical complication rate for pancreas transplants is higher than for any other solid organ transplant.Other pancreas-specific complications include graft pancreatitis (frequently due to pro-curement or reperfusion injury), pancreatic fistulas, and pan-creatic pseudocysts.Anastomotic leaks do not always require a graft pancreatectomy, but arterial pseudoaneurysms, arteriove-nous fistulas, and wound dehiscence may.
In addition, these patients may also have involvement of the mucous membranes and respiratory and intestinal tracts.The associated morbidity, such as sepsis, and mortality rates are relatively high and are a function of the extent of epidermal necrosis.This results in large areas of denuded skin.(Table 72-12) Depending on their size, cutaneous blisters are referred to as vesicles (<1 cm) or bullae (>1 cm). The primary autoimmune blistering disorders include pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid, gestational pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita, linear IgA bullous dermatosis (LABD), and dermatitis herpetiformis (Chap. 73). Vesicles and bullae are also seen in contact dermatitis, both allergic and irritant forms (Chap. 71). When there is a linear arrangement of vesicular lesions, an exogenous cause or herpes zoster should be suspected. Bullous disease secondary to the ingestion of drugs can take one of several forms, including phototoxic eruptions, isolated bullae, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) (Chap. 74). Clinically, phototoxic eruptions resemble an exaggerated sunburn with diffuse erythema and bullae in sun-exposed areas. The most commonly associated drugs are doxycycline, quinolones, thiazides, NSAIDs, voriconazole, and psoralens. The development of a phototoxic eruption is dependent on the doses of both the drug and ultraviolet (UV)-A irradiation. Toxic epidermal necrolysis is characterized by bullae that arise on widespread areas of tender erythema and then slough. This results in large areas of denuded skin. The associated morbidity, such as sepsis, and mortality rates are relatively high and are a function of the extent of epidermal necrosis. In addition, these patients may also have involvement of the mucous membranes and respiratory and intestinal tracts.Severe acute graft-versus-host disease (grade 4), van-comycin-induced LABD, and the acute syndrome of apoptotic panepidermolysis (ASAP) in patients with lupus can also resemble TEN.In erythema multiforme (EM), the primary lesions are pink-red macules and edematous papules, the centers of which may become vesicular.
The degeneration of the axons leads to muscle weakness and atrophy, which is usually fatal.The neurodegenerative disease amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) is associated with an accumulation and abnormal assembly of neurofilaments in motor neuron cell bodies and in the axon, aberrations that may interfere with normal axonal transport.All of these maladies are typified by cell rupture as a consequence of mechanical trauma and a disorganization or clumping of the keratin filament cytoskeleton. Many of the specific mutations that cause these diseases alter the ends of the central rod domain, demonstrating the importance of this particular part of the protein for correct filament assembly. Members of another family of intermediate filaments, called neurofilaments, are found in high concentrations along the axons of vertebrate neurons (Figure 16–70). Three types of neurofilament proteins (NF-L, NF-M, and NF-H) coassemble in vivo, forming heteropolymers. The NF-H and NF-M proteins have lengthy C-terminal tail domains that bind to neighboring filaments, generating aligned arrays with a uniform interfilament spacing. During axonal growth, new neurofilament subunits are incorporated all along the axon in a dynamic process that involves the addition of subunits along the filament length as well as the ends. After an axon has grown and connected with its target cell, the diameter of the axon may increase as much as fivefold. The level of neurofilament gene expression seems to directly control axonal diameter, which in turn influences how fast electrical signals travel down the axon. In addition, neurofilaments provide strength and stability to the long cell processes of neurons. The neurodegenerative disease amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) is associated with an accumulation and abnormal assembly of neurofilaments in motor neuron cell bodies and in the axon, aberrations that may interfere with normal axonal transport. The degeneration of the axons leads to muscle weakness and atrophy, which is usually fatal.However, a causative link between neurofilament pathology and ALS has not been firmly established.basal cell of epidermis Figure 16–69 blistering of the skin caused by a mutant keratin gene.A mutant gene encoding a truncated keratin protein (lacking both the Nand C-terminal domains) was expressed in a transgenic mouse.
advent of colchicine prophylaxis, chronic arthritis of the knee or hip Severehyperpyrexiaand evenfebrileseizuresmaybe seenininfants, wasseenin~5%ofFMFpatientswitharthritis.Chronicsacroiliitiscan andfeverissometimestheonlymanifestationofFMFinyoungchildren.Before the If measured, fever is nearly always present throughout FMF attacks.repeated arthritic attacks, radiographic changes are rare.If [IL]1β-convertingenzyme),andtherebyIL-1βsecretion.Micebearing such patients undergo exploratory laparotomy, a sterile, neutrophilFMF-associated pyrin mutations exhibit inflammation and excessive rich peritoneal exudate is present, sometimes with adhesions from IL-1 production. previous episodes. Ascites is rare. Pleural attacks are usually manifested by unilateral, sharp, stabbing chest pain. Radiographs may show atelectasis and sometimes an effusion. If performed, thoracentesis demonstrates an exudative Febrile episodes in FMF may begin even in early infancy; 90% of fluid rich in neutrophils. After repeated attacks, pleural thickening patients have had their first attack by age 20. Typical FMF episodes may develop. generally last 24–72 h, with arthritic attacks tending to last somewhat FMF arthritis is most frequent among individuals homozygous for longer. In some patients, the episodes occur with great regularity, but the M694V mutation, which is especially common in the non-Ashkemore often, the frequency of attacks varies over time, ranging from as nazi Jewish population. Acute arthritis in FMF is usually monoarticuoftenasonceeveryfewdaystoremissionslastingseveralyears.Attacks lar, affecting the knee, ankle, or hip, although other patterns can be are often unpredictable, although some patients relate them to physi-seen, particularly inchildren. Largesterileeffusionsrichin neutrophils cal exertion, emotional stress, or menses; pregnancy may be associated are frequent, without commensurate erythema or warmth. Even after with remission. repeated arthritic attacks, radiographic changes are rare. Before the If measured, fever is nearly always present throughout FMF attacks. advent of colchicine prophylaxis, chronic arthritis of the knee or hip Severehyperpyrexiaand evenfebrileseizuresmaybe seenininfants, wasseenin~5%ofFMFpatientswitharthritis.Chronicsacroiliitiscan andfeverissometimestheonlymanifestationofFMFinyoungchildren.In the United States, FMF patients are much more likely to have arthralgia than arthritis.The most characteristic cutaneous manifestation of FMF is erysipelas-like erythema, a raised erythematous rash that most commonly occurs on the dorsum of the foot, ankle, or lower leg alone or in combination with abdominal pain, pleurisy, or arthritis.
No drugs are cleared by the FDA to treat stress incontinence.The use of these agents in the treatment of stress urinary incontinence appears to be more limited than originally thought (58).relatively pure stress incontinence, no history of recurrent urinary tract infections, and no serious contraindications to bacteriuria (e.g., artificial heart valves). The FemSoft device was U.S. Food and Drug Administration (FDA) approved in 1997 and is the only urethral insert that is available in the United States. Several other urethral inserts and urethral occlusion devices were marketed with good effectiveness but were withdrawn from the market. In a 5-year, multicenter trial involving 150 women with a mean follow-up of 15 months, a statistically significant reduction in incontinence episodes and pad weight were observed with 93% of the women having a negative pad test at 12 months. However, urinary tract infections were common and found in 31.3% of the subjects (56). Urethral inserts have not developed a widespread acceptance but may offer a viable treatment option for some select patients. The tone of the urethra and bladder neck is maintained in large part by α-adrenergic activity from the sympathetic nervous system. For this reason, many pharmacologic agents are used with varying degrees of success to treat stress incontinence. These drugs include imipramine (which has a concomitant relaxing effect on the detrusor), ephedrine, pseudoephedrine, phenylpropanolamine, and norepinephrine. Many of these compounds increase vascular tone and may, therefore, lead to problems with hypertension, a condition that afﬂicts many postmenopausal women with stress incontinence. There is an increased risk for hemorrhagic cerebral vascular accident in women taking phenylpropanolamine, and while the risk is very low, it is not possible to predict who is at risk for this complication (57). The use of these agents in the treatment of stress urinary incontinence appears to be more limited than originally thought (58). No drugs are cleared by the FDA to treat stress incontinence.In early uncontrolled case series, women using various estrogen preparations experienced less incontinence.However, in several large randomized trials, women assigned to receive estrogen and progesterone did not have less leakage, and were more likely to experience the onset of incontinence or worsening of baseline symptoms (59).
Bleeding occurring less frequently than an internal of 90 days is abnormal, even in the first gynecologic year after menarche (51).One study found that one-third of individuals who estimated their cycles to be moderate or light had bleeding in excess of 80 mL/cycle, whereas nearly one-half of those who described the bleeding as heavy had ﬂow less than 80 mL/cycle (59). In addition, the amount of menstrual blood contained in each tampon or pad may vary both within brands as well as from one brand to another (57). However, changing a pad hourly, clots larger than “50 pence size,” and requiring a change overnight are associated with a measured volume of greater than 80 mL (58). The transition from anovulatory to ovulatory cycles during adolescence takes place during the first several years after menarche. It results from the so-called maturation of the hypothalamic–pituitary–ovarian axis, characterized by positive feedback mechanisms in which a rising estrogen level triggers a surge of luteinizing hormone and ovulation. Most adolescents have ovulatory cycles by the end of their second year of menstruation, although most cycles (even anovulatory ones) remain within a rather narrow range of approximately 21 to 42 days. Table 14.5 Parameters for Normal Menstrual Cycles in Adolescents From Hillard PJ. Menstruation in young girls: a clinical perspective. Obstet Gynecol 2002;99:655–662. Table 14.6 Conditions Associated with Anovulation and Abnormal Bleeding Androgen excess syndromes (e.g., polycystic ovary syndrome [PCOS]) Differential Diagnosis of Adolescent Abnormal Bleeding Cycles that are longer than 42 days, bleeding that occurs more frequently than 21 days, and bleeding that lasts more than 7 days should be considered abnormal, particularly after the first 2 years from the onset of menarche. Bleeding occurring less frequently than an internal of 90 days is abnormal, even in the first gynecologic year after menarche (51).However, consideration should be given to an evaluation of possible causes of abnormal menses (particularly underlying causes of anovulation such as androgen excess syndromes or causes of oligomenorrhea such as eating disorders) for girls whose cycles are consistently outside normal ranges or whose cycles were previously regular and become irregular (60,61).
Defects in the erythroid gene shown in Fig.As and Xp11.2 (ALAS2), respectively.Source: From KE Anderson et al: Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias, in The Metabolic and Molecular Bases of Inherited Diseases, CR Scriver et al (eds). New York, McGraw-Hill, 2001, pp 2991–3062. aNonspecific increases in zinc protoporphyrins are common in other porphyrias. Rule out other causes of elevated ALA; ↓↓RBC ALA dehydratase activity (<10%); ALA dehydratase mutation analysis Measure RBC HMB synthase: normal activity Measure RBC HMB synthase: normal activity RBC URO decarboxylase activity: half-normal in familial PCT (~20% of all PCT cases); substantially deficient in HEP URO decarboxylase mutation analysis: mutation(s) present in familial PCT (heterozygous) and HEP (homozygous) The Porphyrias Abbreviations: ADP, 5-ALA dehydratase-deficient porphyria; AIP, acute intermittent porphyria; ALA, 5-aminolevulinic acid; CEP, congenital erythropoietic porphyria; COPRO I, coproporphyrin I; COPRO III, coproporphyrin III; EPP, erythropoietic protoporphyria; F, fecal; HCP, hereditary coporphyria; HEP, ; ISOCOPRO, isocoproporphyrin; P, plasma; PBG, porphobilinogen; PCT, porphyria cutanea tarda; PROTO, protoporphyrin IX; RBC, erythrocytes; U, urine; URO I, uroporphyrin I; URO III, uroporphyrin III; VP, variegate porphyria; XLP, X-linked protoporphyria. Source: Based on KE Anderson et al: Ann Intern Med 142:439, 2005. FIGURE 430-2 The heme biosynthetic pathway showing the eight enzymes and their substrates and products. Four of the enzymes are localized in the mitochondria and four in the cytosol. the synthesis of CYPs, which are especially abundant in the liver (e.g., housekeeping) and erythroid-specific forms of ALA synthase are endoplasmic reticulum, and turn over more rapidly than many other encoded by separate genes located on chromosome 3p21.1 (ALAS1) hemoproteins, such as the mitochondrial respiratory cytochromes. As and Xp11.2 (ALAS2), respectively. Defects in the erythroid gene shown in Fig.Recently, gain-of-function mutations in the last exon (11) of known as porphyrinogens).At least in humans, these intermediates do ALAS2 that increase its activity have been shown to cause an X-linked not accumulate in significant amounts under normal conditions or form of EPP, known as X-linked protoporphyria (XLP).have important physiologic functions.
The goals of such ther-apy are to decrease the risk of an ipsilateral recurrence after breast conservation therapy for DCIS and to decrease the risk of a primary invasive breast cancer or a contralateral breast cancer event.Cataract surgery is more frequently performed in patients receiving tamoxifen. The Stockholm trial showed that 5 years of tamoxifen was associated with a significant reduction in locoregional recurrences and distant metastasis in postmenopausal women with ER-positive breast cancer.332 However, an increase in endometrial cancers was observed with long-term tamoxifen use. The NSABP B14 trial evaluated 10 years of tamoxifen compared to 5 years.333 However, the study was terminated based on interim analyses indicating no addi-tional benefit from tamoxifen beyond 5 years. The ATLAS trial also evaluated the use of tamoxifen for 5 years vs. 10 years in nearly 13,000 women across the world. This study showed that continuing tamoxifen for 10 years vs. 5 years produced a significant reduction in recurrence and mortality.334 Interestingly, the benefit was not seen in the second 5 years (i.e., years 5–9) while the patients were on treatment, but it was seen from years 10 to 15. One reason the NSABP B14 study was led to conclude that 10 years of tamoxifen was not beneficial was that the follow-up time was shorter. Results of the ATLAS study were also corroborated by the aTTom study. Similarly, extended adjuvant therapy with letrozole after 5 years of tamoxifen was shown to improve disease-free survival without improvement in overall survival except in node-positive patients.335Tamoxifen therapy is also considered for women with DCIS that is found to be ER-positive. The goals of such ther-apy are to decrease the risk of an ipsilateral recurrence after breast conservation therapy for DCIS and to decrease the risk of a primary invasive breast cancer or a contralateral breast cancer event.With the use of aromatase inhibitors in postmenopausal women, use of adjuvant tamoxifen has increasingly been limited to premenopausal women.Aromatase Inhibitors.In postmenopausal women, aromatase inhibitors are now considered first-line therapy in the adjuvant setting.
A Veau III cleft is a complete unilateral cleft of primary and secondary pal-ates, in which the cleft extends through the lip, the alveolus, the entire length of the nasal floor on the cleft side, and the midline of the soft palate.The soft palate, or velum, together with lateral and posterior pharyngeal walls, can be conceptualized as a valve that regulates the passage of air through the nasopharynx. The paired levator veli palatini muscles descend from the cranial base and decussate in the midline to form a sling within the soft palate. This sling acts to elevate the velum against the posterior pharyngeal wall, effectively closing the velopharyngeal port. In patients with cleft palate, the levator muscles are unable to cross the midline. Instead, they run parallel to the cleft margin and insert aberrantly into the posterior edge of the hard palate (Fig. 45-28A,B). Air is allowed to leak through the nose dur-ing attempts to suck or speak. This inability to build negative or positive intraoral pressure makes either task difficult, if not impossible. The tensor veli palatini muscles, which normally function to vent and drain the Eustachian tubes, are also dis-rupted in cleft anatomy. Eustachian tube dysfunction predis-poses patients to frequent bouts of otitis media, which can lead to permanent hearing loss if left untreated.20The most clinically useful system to describe cleft pal-ate morphology is the Veau classification. A Veau I cleft is midline and limited to the soft palate alone, whereas a Veau II cleft may extend further anteriorly to involve the midline of the posterior hard palate (the “secondary palate”). A Veau III cleft is a complete unilateral cleft of primary and secondary pal-ates, in which the cleft extends through the lip, the alveolus, the entire length of the nasal floor on the cleft side, and the midline of the soft palate.45-29A,B).Not included in the Veau classification is the submucous cleft palate, which occurs when there is clefting of the soft palate musculature beneath intact mucosa.
Although these adults may be sources of support for the single parent, they also may criticize the parent, decreasing confidence in parenting skills.These parents must also rely to a greater extent on other adults for child care.Thus the frequency of children living in poverty is three to five times higher in single-parent families.The diversity in the structure of the family in the United States has increased dramatically; less than half of children now live in the traditional nuclear family. Today children may live with unmarried parents, single parents of either gender, a parent and a stepparent, grandparents, parents living as a same-sex couple, or foster care families. There is little evidence that family structure alone is a significant predictor of child health or development. Regardless of family structure, the presence of a loving adult or adults serving as a parent or parents committed to fulfilling a child’s physical, emotional, and socialization needs is the best predictor of good health and development. Different family structures create different types of family stresses. At any one point in time, approximately 30% of children are living in single parent families, and more than 40% of children are born to unmarried mothers. In some cases this is the mother’s choice, but often times this results from a young woman’s unplanned pregnancy. Children may also live in single-parent families because of divorce or the death of a parent (see Chapter 26). Although most single parent families are still headed by mothers, single-father families are increasing and in 2009 nearly 5% of children lived in single-father families. Single parents often have limited financial resources and social supports. For households headed by single mothers, the median income is only 40% of the income of two-parent families and for single fathers it is only 60% of the income of two parent families. Thus the frequency of children living in poverty is three to five times higher in single-parent families. These parents must also rely to a greater extent on other adults for child care. Although these adults may be sources of support for the single parent, they also may criticize the parent, decreasing confidence in parenting skills.Single parents are likely to have less time for a social life or other activities, which may increase their isolation.When the increased burdens of being a single parent are associated with exhaustion, isolation, and depression, developmental and behavioral problems in the child are more likely.When the parent is a teenage mother, problems of parenting may be exacerbated further (see Section 12).
Intracellular ADP, resulting from the breakdown of ATP, enhances mitochondrial ATP production.Acetyl-CoA enters the citric acid (Krebs) cycle to produce ATP by oxidative phosphorylation within the mitochondria; ATP then enters the cytoplasm from the mitochondrial compartment.FFAs are converted to acyl-CoA in the cytoplasm and acetyl-CoA in the mitochondria.CHAPTER 265e Basic Biology of the Cardiovascular System FIGURE 265e-9 Interactions in the intact circulation of preload, contractility, and afterload in producing stroke volume. Stroke volume combined with heart rate determines cardiac output, which, when combined with peripheral vascular resistance, determines arterial pressure for tissue perfusion. The characteristics of the arterial system also contribute to afterload, an increase that reduces stroke volume. The interaction of these components with carotid and aortic arch baroreceptors provides a feedback mechanism to higher medullary and vasomotor cardiac centers and to higher levels in the central nervous system to effect a modulating influence on heart rate, peripheral vascular resistance, venous return, and contractility. (From MR Starling: Physiology of myocardial contraction, in Atlas of Heart Failure: Cardiac Function and Dysfunction, 3rd ed, WS Colucci and E Braunwald [eds]. Philadelphia: Current Medicine, 2002, pp 19–35.) 265e-10 Normal as from the cell’s breakdown of its glycogen stores Disorders of the Cardiovascular System FIGURE 265e-10 The responses of the left ventricle to increased afterload, (glycogenolysis). These two principal sources of acetyl coenzyme A in cardiac muscle vary reciprocally. Glucose is broken down in the cytoplasm into a three-carbon product, pyruvate, which passes into the mitochondria, where it is metabolized to the two-carbon fragment, acetyl-CoA, and undergoes oxidation. FFAs are converted to acyl-CoA in the cytoplasm and acetyl-CoA in the mitochondria. Acetyl-CoA enters the citric acid (Krebs) cycle to produce ATP by oxidative phosphorylation within the mitochondria; ATP then enters the cytoplasm from the mitochondrial compartment. Intracellular ADP, resulting from the breakdown of ATP, enhances mitochondrial ATP production.In the fed state, with elevations of blood increased preload, and increased and reduced contractility are shown in the glucose and insulin, glucose oxidation increases and pressure-volume plane.Left.Effects of increases in preload and afterload on the FFA oxidation subsides.Increased cardiac work, the pressure-volume loop.
In some patients, an anterior medi-astinotomy (i.e., Chamberlain procedure) may be ideal for an anterior tumor or a tumor with significant parasternal extension.For tumors of the anterior or posterior medi-astinum, a left or right VATS approach often allows safe and adequate surgical biopsies.New York, NY: Elsevier/Churchill Livingstone; 2002.Surgical Biopsies and Resection of Mediastinal MassesFor tumors of the mediastinum that are not amenable to an endo-scopic or CT-guided needle biopsy or that do not yield sufficient tissue for diagnosis, a surgical biopsy is indicated. The defini-tive approach to a surgical biopsy of the anterior mediastinum is through a median sternotomy. At the time of sternotomy, if the lesion is easily resectable, it should be completely removed. Given the invasiveness of the procedure and the inability in some patients to obtain a definitive diagnosis by frozen section, less invasive procedures are preferable if the lesion is large or if the CT scan or history suggests that surgery is not the best definitive treatment.Masses in the paratracheal region are easily biopsied by mediastinoscopy. For tumors of the anterior or posterior medi-astinum, a left or right VATS approach often allows safe and adequate surgical biopsies. In some patients, an anterior medi-astinotomy (i.e., Chamberlain procedure) may be ideal for an anterior tumor or a tumor with significant parasternal extension.Pain scores were significantly better in the VATS approach.149 These reports and others support application of VATS for the majority of ante-rior mediastinal masses.Other minimally invasive approaches are under study.For example, good results have been reported using a cervical incision with a sternal retractor for thymus removal.
Invasive aspergillosis is not an AIDS-defining illness and is generally not seen in patients with AIDS in the absence of neutropenia or administration of glucocorticoids.While serologic testing is of value in the immunocompetent host, serologies are negative in 25% of HIV-infected patients with coccidioidal infection.One may also see nodules, cavities, pleural effusions, and hilar adenopathy.This may be discontinued in patients in whom cART induces a sustained suppression of viral replication and an increase in CD4+ T cell count to >100/μL for ≥6 months. Rhodococcus equi is a gram-positive, pleomorphic, acid-fast, nonspore-forming bacillus that can cause pulmonary and/or disseminated infection in patients with advanced HIV infection. Fever and cough are the most common presenting signs. Radiographically one may see cavitary lesions and consolidation. Blood cultures are often positive. Treatment is based on antimicrobial sensitivity testing. Fungal infections of the lung, in addition to PCP, can be seen in patients with AIDS. Patients with pulmonary cryptococcal disease present with fever, cough, dyspnea, and, in some cases, hemoptysis. A focal or diffuse interstitial infiltrate is seen on chest x-ray in >90% of patients. In addition, one may see lobar disease, cavitary disease, pleural effusions, and hilar or mediastinal adenopathy. More than half of patients are fungemic, and 90% of patients have concomitant CNS infection. Coccidioides immitis is a mold that is endemic in the southwest United States. It can cause a reactivation pulmonary syndrome in patients with HIV infection. Most patients with this condition will have CD4+ T cell counts <250/μL. Patients present with fever, weight loss, cough, and extensive, diffuse reticulonodular infiltrates on chest x-ray. One may also see nodules, cavities, pleural effusions, and hilar adenopathy. While serologic testing is of value in the immunocompetent host, serologies are negative in 25% of HIV-infected patients with coccidioidal infection. Invasive aspergillosis is not an AIDS-defining illness and is generally not seen in patients with AIDS in the absence of neutropenia or administration of glucocorticoids.Primary pulmonary infection of the lung may be seen with histoplasmosis.The most common pulmonary manifestation of histoplasmosis, however, is in the setting of disseminated disease, presumably due to reactivation.In this setting respiratory symptoms are usually minimal, with cough and dyspnea occurring in 10–30% of patients.
Dominant masses or areas of firmness, irregular-ity, and asymmetry suggest the possibility of a breast cancer, particularly in the older male.Mammography and ultrasonography are used to differentiate breast tissues.In the nonobese male, breast tissue measuring at least 2 cm in diameter must be present before a diagnosis of gynecomastia may be made.Primary testicular failure a. Klinefelter’s syndrome (XXY) b. Reifenstein’s syndrome c. Rosewater-Gwinup-Hamwi familial gynecomastia d. Kallmann syndrome e. Kennedy’s disease with associated gynecomastia f. Eunuchoidal state (congenital anorchia) g. Hereditary defects of androgen biosynthesis h. Adrenocorticotropic hormone deficiency 2. Secondary testicular failure a. Trauma b. Orchitis c. Cryptorchidism d. Irradiation C. Renal failure III. Pharmacologic causes IV. Systemic diseases with idiopathic mechanismsthe ovaries and involution of the ducts and alveoli of the breast. The surrounding fibrous connective tissue increases in density, and breast tissues are replaced by adipose tissues (Fig. 17-9D).GynecomastiaGynecomastia refers to an enlarged breast in the male.20 Physi-ologic gynecomastia usually occurs during three phases of life: the neonatal period, adolescence, and senescence. Common to each of these phases is an excess of circulating estrogens in relation to circulating testosterone. Neonatal gynecomastia is caused by the action of placental estrogens on neonatal breast tissues, whereas in adolescence, there is an excess of estradiol relative to testosterone, and with senescence, the circulating testosterone level falls, which results in relative hyperestrin-ism. In gynecomastia, the ductal structures of the male breast enlarge, elongate, and branch with a concomitant increase in epithelium. During puberty, the condition often is unilateral and typically occurs between ages 12 and 15 years. In contrast, senescent gynecomastia is usually bilateral. In the nonobese male, breast tissue measuring at least 2 cm in diameter must be present before a diagnosis of gynecomastia may be made. Mammography and ultrasonography are used to differentiate breast tissues. Dominant masses or areas of firmness, irregular-ity, and asymmetry suggest the possibility of a breast cancer, particularly in the older male.However, the hypoandro-genic state of Klinefelter’s syndrome (XXY), in which gyneco-mastia is usually evident, is associated with an increased risk of breast cancer.
D. Divided into acute and chronic forms 1.C. Antibody-bound platelets are consumed by splenic macrophages, resulting in thrombocytopenia.Most common cause of thrombocytopenia in children and adults B. Autoantibodies are produced by plasma cells in the spleen.IMMUNE THROMBOCYTOPENIC PURPURA (ITP) A. Autoimmune production oflgG against platelet antigens (e.g., GPIIb/IIIa) 1.TXA2 is synthesized by platelet cyclooxygenase (COX) and released; promotes platelet aggregation D. Step 4-Platelet aggregation 1. Platelets aggregate at the site of injury via GPIIb/llla using fibrinogen (from plasma) as a linking molecule; results in formation of platelet plug 2. Platelet plug is weak; coagulation cascade (secondary hemostasis) stabilizes it. II. DISORDERS OF PRIMARY HEMOSTASIS A. Usually due to abnormalities in platelets; divided into quantitative or qualitative disorders B. Clinical features include mucosa! and skin bleeding. 1. Symptoms of mucosa! bleeding include epistaxis (most common overall symptom), hemoptysis, GI bleeding, hematuria, and menorrhagia. Intracranial bleeding occurs with severe thrombocytopenia. 2. Symptoms of skin bleeding include petechiae (1-2 mm, Fig. 4.1), purpura (> 3 mm), ecchymoses (> 1 cm), and easy bruising; petechiae are a sign of thrombocytopenia and are not usually seen with qualitative disorders. pathoma.com C. Useful laboratory studies include 1. Platelet count-normal 150-400 K/µL; < 50 K/µL leads to symptoms. 2. Bleeding time-normal 2-7 minutes; prolonged with quantitative and qualitative platelet disorders 3. Blood smear-used to assess number and size of platelets 4. Bone marrow biopsy-used to assess megakaryocytes, which produce platelets III. IMMUNE THROMBOCYTOPENIC PURPURA (ITP) A. Autoimmune production oflgG against platelet antigens (e.g., GPIIb/IIIa) 1. Most common cause of thrombocytopenia in children and adults B. Autoantibodies are produced by plasma cells in the spleen. C. Antibody-bound platelets are consumed by splenic macrophages, resulting in thrombocytopenia. D. Divided into acute and chronic forms 1.Chronic form arises in adults, usually women of childbearing age.May be primary or secondary (e.g., SLE).May cause short-lived thrombocytopenia in offspring since antiplatelet IgG can cross the placenta.E. Laboratory findings include 1...J.. platelet count, often < 50 K/µL 2.Normal PT/PTT-Coagulation factors are not affected.3.F. Initial treatment is corticosteroids.
It is recommended that the live yellow fever vaccine not be given to HIV-infected travelers.Between 18% and 58% of symptomatic HIV-infected vaccinees develop adequate measles antibody titers, and 50–100% of asymptomatic HIV-infected persons seroconvert.Immunizations All of the HIV-infected traveler’s routine immunizations should be up to date (Chap. 148). The response to immunization may be impaired at CD4+ T cell counts of <200/μL and in some cases at even higher counts. Thus HIV-infected persons should be vaccinated as early as possible to ensure adequate immune responses. For patients receiving antiretroviral therapy, at least 3 months must elapse before regenerated CD4+ T cells can be considered fully functional; therefore, vaccination of these patients should be delayed. However, when the risk of illness is high or the sequelae of illness are serious, immunization is recommended. In certain circumstances, it may be prudent to check the adequacy of the serum antibody response before departure. Because of the increased risk of infections due to Streptococcus pneumoniae and other bacterial pathogens that cause pneumonia after influenza, the conjugate pneumococcal vaccine (Prevnar 13) followed by the 23-valent polysaccharide vaccine (Pneumovax) as well as influenza vaccine should be administered. The estimated rates of response to influenza vaccine are >80% among persons with asymptomatic HIV infection and <50% among those with AIDS. In general, live attenuated vaccines are contraindicated for persons with immune dysfunction. Because measles (rubeola) can be a severe or lethal infection in HIV-positive patients, these patients should receive the measles vaccine (or the combination MMR vaccine) unless the CD4+ T cell count is <200/μL. Between 18% and 58% of symptomatic HIV-infected vaccinees develop adequate measles antibody titers, and 50–100% of asymptomatic HIV-infected persons seroconvert. It is recommended that the live yellow fever vaccine not be given to HIV-infected travelers.Nonetheless, if the CD4+ T cell count is <200/μL, an alternative itinerary that poses no risk of exposure to yellow fever is recommended.If the traveler is passing through or traveling to an area where the vaccine is required but the disease risk is low, a physician’s waiver should be issued.
37.23).In the most common variety, the adult granulosa cells show a tendency to arrange themselves in small clusters or rosettes around a central cavity, so there is a resemblance to primordial follicles (i.e., Call-Exner bodies) (Fig.A. Stromal luteoma B. Leydig cell tumor C. Steroid cell tumor, not otherwise classified Granulosa-stromal cell tumors include granulosa cell tumors, thecomas, and fibromas. The granulosa cell tumor is a low-grade malignancy; rarely, thecomas and fibromas have morphologic features of malignancy and may be referred to as fibrosarcomas. Granulosa cell tumors, which secrete estrogen, are seen in women of all ages. They are found in prepubertal girls in 5% of cases; the remainder are found in women throughout their reproductive and postmenopausal years (422). Granulosa cell tumors are bilateral in only 2% of patients. Granulosa cell tumors range from a few millimeters to 20 cm or more in diameter. The tumors are rarely bilateral and have a smooth, lobulated surface. The solid portions of the tumor are granular, frequently trabeculated, and yellow or gray-yellow in color. After clear cell carcinoma, the granulosa-theca cell tumor is probably the most inaccurately diagnosed tumor of the female gonad. Of 477 ovarian tumors from the Emil Novak Ovarian Tumor Registry diagnosed initially as granulosa-theca cell tumors, almost 15% were reclassified after histologic review. Lesions misdiagnosed as granulosa cell tumors included primary or metastatic carcinomas, teratoid tumors, and poorly differentiated mesothelial tumors (419). The classic adult granulosa cell is round or ovoid with scant cytoplasm. The nucleus contains compact, finely granular chromatin and is either euchromatic or hypochromatic (3). “Coffee bean” grooved nuclei are characteristic; mitotic figures may be present, but numerous mitotic figures should prompt consideration for poorly differentiated or undifferentiated carcinoma. In the most common variety, the adult granulosa cells show a tendency to arrange themselves in small clusters or rosettes around a central cavity, so there is a resemblance to primordial follicles (i.e., Call-Exner bodies) (Fig. 37.23).In children and adolescents, the granular cell tumors are often cystic, contain luteinized cells, and can be associated with precocious puberty.Juvenile granulosa cell tumors, so named because of their tendency to occur in younger patients, feature rounder, more hyperchromatic nuclei and may contain numerous mitotic figures.
Other sites in which electrical stimulation is effective in suppressing nociceptive responses are the rostroventral medulla (nucleus raphe magnus and adjacent reticular formation) and the dorsolateral pontine tegmentum.In human subjects, stimulation of the midbrain periaqueductal gray matter through stereotactically implanted electrodes can also produced a state of analgesia.These investigators have sought to develop an imaging “pain signature” that could, in the future, objectively measure the human pain response. Moreover, physical pain in their experiments could be differentiated from social and emotional pain. An important contribution to our understanding of pain has been the discovery of a neuronal analgesia system that can be activated by the administration of opiates or by naturally occurring brain substances that share the properties of opiates. This endogenous system was first demonstrated by Reynolds, who found that stimulation of the ventrolateral periaqueductal gray matter in the rat produced a profound analgesia without altering behavior or motor activity. Subsequently, stimulation of other discrete sites in the medial and caudal regions of the diencephalon and rostral bulbar nuclei (notably raphe magnus and paragigantocellularis) was shown to have the same effect. Under the influence of such electrical stimulation, the animal could be operated on without anesthesia and move around in an undisturbed manner despite the administration of noxious stimuli. Investigation disclosed that the effect of stimulation-produced analgesia (SPA) is inhibition of the neurons of Rexed laminae I, II, and V of the dorsal horn, which are the neurons activated by noxious stimuli. In human subjects, stimulation of the midbrain periaqueductal gray matter through stereotactically implanted electrodes can also produced a state of analgesia. Other sites in which electrical stimulation is effective in suppressing nociceptive responses are the rostroventral medulla (nucleus raphe magnus and adjacent reticular formation) and the dorsolateral pontine tegmentum.Ascending pathways from the dorsal horn, conveying noxious somatic impulses, are also important in activating the modulatory network.Opiates act preand postsynaptically on the neurons of laminae I and V of the dorsal horn, suppressing afferent pain impulses from both the A-d and C fibers as previously discussed.Furthermore, these effects can be reversed by the opioid antagonist naloxone.
The third and fourth palmar interossei originate from the lateral surfaces of metacarpals IV and V and insert into the lateral sides of the respective extensor hoods.The second palmar interosseous muscle originates from the medial surface of metacarpal II and inserts into the medial side of the extensor hood of the index finger.In addition to generating flexion and extension movements of the fingers through their attachments to the extensor hoods, the dorsal interossei are the major abductors of the index, middle, and ring fingers, at the metacarpophalangeal joints (Table 7.15). The middle finger can abduct medially and laterally with respect to the long axis of the middle finger and consequently has a dorsal interosseous muscle on each side. The thumb and little finger have their own abductors in the thenar and hypothenar muscle groups, respectively, and therefore do not have dorsal interossei. The radial artery passes between the two heads of the first dorsal interosseous muscle as it passes from the anatomical snuffbox on the posterolateral side of the wrist into the deep aspect of the palm. The three (or four) palmar interossei are anterior to the dorsal interossei, and are unipennate muscles originating from the metacarpals of the digits with which each is associated (Fig. 7.105). The first palmar interosseous muscle is rudimentary and often considered part of either the adductor pollicis or the flexor pollicis brevis. When present, it originates from the medial side of the palmar surface of metacarpal I and inserts into both the base of the proximal phalanx of the thumb and into the extensor hood. A sesamoid bone often occurs in the tendon attached to the base of the phalanx. The second palmar interosseous muscle originates from the medial surface of metacarpal II and inserts into the medial side of the extensor hood of the index finger. The third and fourth palmar interossei originate from the lateral surfaces of metacarpals IV and V and insert into the lateral sides of the respective extensor hoods.The palmar interossei adduct the thumb, index, ring, and little fingers with respect to a long axis through the middle finger.The movements occur at the metacarpophalangeal joints.Because the muscles insert into the extensor hoods, they also produce complex flexion and extension movements of the digits (Table 7.15).
The effect on most of the known targets is to inactivate them; but the targets are such that these actions of Akt all conspire to enhance cell survival and growth, as illustrated for one cell survival pathway in Figure 15–53.Akt phosphorylates various target proteins at the plasma membrane, as well as in the cytosol and nucleus.Once activated, PI(3,4,5)P3 PI(4,5)P2 PH domains CYTOSOL activated receptor tyrosine kinase activated PI 3-kinase PDK1 Akt phosphorylation and activation of Akt by PDK1 and mTOR dissociation active Akt Bad inactive apoptosis-inhibitory protein inactivated Bad INHIBITION OF APOPTOSIS PHOSPHORYLATION OF Bad 14-3-3 protein mTOR (in complex 2)P P P P P P P P P P P P P P P P P P Figure 15–53 One way in which signaling through PI 3-kinase promotes cell survival. An extracellular survival signal activates an RTK, which recruits and activates PI 3-kinase. The PI 3-kinase produces PI(3,4,5)P3, which serves as a docking site for two serine/threonine kinases with PH domains—Akt and the phosphoinositide-dependent kinase PDK1—and brings them into proximity at the plasma membrane. The Akt is phosphorylated on a serine by a third kinase (usually mTOR in complex 2), which alters the conformation of the Akt so that it can be phosphorylated on a threonine by PDK1, which activates the Akt. The activated Akt now dissociates from the plasma membrane and phosphorylates various target proteins, including the Bad protein. When unphosphorylated, Bad holds one or more apoptosis-inhibitory proteins (of the Bcl2 family—discussed in Chapter 18) in an inactive state. Once phosphorylated, Bad releases the inhibitory proteins, which now can block apoptosis and thereby promote cell survival. As shown, the phosphorylated Bad binds to a ubiquitous cytosolic protein called 14-3-3, which keeps Bad out of action. Akt phosphorylates various target proteins at the plasma membrane, as well as in the cytosol and nucleus. The effect on most of the known targets is to inactivate them; but the targets are such that these actions of Akt all conspire to enhance cell survival and growth, as illustrated for one cell survival pathway in Figure 15–53.TOR was originally identified in yeasts in genetic screens for rapamycin resistance; in mammalian cells, it is called mTOR, which exists in cells in two functionally distinct multiprotein complexes.
274 and 276.Intracardiac electrocardiography and electrophysiologic testing are discussed in Chaps.FIGURE 268-3 The six frontal plane (A) and six horizontal plane (B) leads provide a P WAVE ambulatory ECG (Holter) recordings usually employ only one or two modified leads.+ V4 deflection will be recorded.268-3B).The QT interval includes both ventricular depolarization and repolarization times and varies inversely with the heart rate. A rate-related (“corrected”) QT interval, QTc, can be calculated as QT/√RR and normally is ≤0.44 s. (Some references give QTc upper normal limits as 0.43 s in men and 0.45 s in women. Also, a number of different formulas have been proposed, without consensus, for calculating the QTc.) The QRS complex is subdivided into specific deflections or waves. If the initial QRS deflection in a particular lead is negative, it is termed a Q wave; the first positive deflection is termed an R wave. A negative deflection after an R wave is an S wave. Subsequent positive or negative waves are labeled R′ and S′, respectively. Lowercase letters (qrs) are used for waves of relatively small amplitude. An entirely negative QRS complex is termed a QS wave. The 12 conventional ECG leads record the difference in potential between electrodes placed on the surface of the body. These leads are divided into two groups: six limb (extremity) leads and six chest (precordial) leads. The limb leads record potentials transmitted onto the frontal plane (Fig. 268-3A), and the chest leads record potentials transmitted onto the horizontal plane (Fig. 268-3B). + V4 deflection will be recorded. FIGURE 268-3 The six frontal plane (A) and six horizontal plane (B) leads provide a P WAVE ambulatory ECG (Holter) recordings usually employ only one or two modified leads. Intracardiac electrocardiography and electrophysiologic testing are discussed in Chaps. 274 and 276.If the mean orientation + of the depolarization vector is at right angles to a particu lar lead axis, a biphasic (equally positive and negative) three-dimensional representation of cardiac electrical activity.The spatial orientation and polarity of the six frontal plane leads is represented on the hexaxial diagram (Fig.268-4).The six chest leads (Fig.
Case 4: Rapid Heart Rate, Headache, and Sweating Patient Presentation: BE is a 45-year-old woman who presents with concerns about sudden (paroxysmal), intense, brief episodes of headache, sweating (diaphoresis), and a racing heart (palpitations).How do hemolytic anemias differ from nutritional anemias?Q3.Blood was drawn for testing. Results of tests on LT’s blood: The test for blood in his stool (occult blood test) was negative. Results of follow-up tests (obtained several days after the appointment) included the following: H = High; L = Low. Diagnosis: LT has vitamin C deficiency with a microcytic, hypochromic anemia secondary to the deficiency. Treatment: LT was prescribed vitamin C (as oral ascorbic acid) and iron (as oral ferrous sulfate) supplements. He will also be referred to social services. Prognosis: The prognosis for recovery is excellent. Case-Related Questions: Choose the ONE best answer. Q1. Which of the following statements about vitamin C is correct? Vitamin C is: A. a competitor of iron absorption in the intestine. B. a fat-soluble vitamin with a 3-month supply typically stored in adipose tissue. C. a coenzyme in several enzymic reactions such as the hydroxylation of proline. D. required for the cross-linking of collagen. Q2. In contrast to the microcytic anemia characteristic of iron deficiency (common in older adults), a macrocytic anemia is seen with deficiencies of vitamin B12 and/or folic acid. These vitamin deficiencies are also common in older adults. Which of the following statements concerning these vitamins is correct? A. An inability to absorb B12 results in pernicious anemia. B. Both vitamins cause changes in gene expression. C. Folic acid plays a key role in energy metabolism in most cells. D. Treatment with methotrexate can result in toxic levels of the coenzyme form of folic acid. E. Vitamin B12 is the coenzyme for enzymes catalyzing amino acid deaminations, decarboxylations, and transaminations. Q3. How do hemolytic anemias differ from nutritional anemias? Case 4: Rapid Heart Rate, Headache, and Sweating Patient Presentation: BE is a 45-year-old woman who presents with concerns about sudden (paroxysmal), intense, brief episodes of headache, sweating (diaphoresis), and a racing heart (palpitations).They last from 2 to 10 minutes, during which time she feels quite anxious.During the attacks, it feels as though her heart is skipping beats (arrhythmia).At first, she thought the attacks were related to recent stress at work and maybe even menopause.The last time it happened, she was in a pharmacy and had her blood pressure taken.She was told it was 165/110 mm Hg.
This loss of declarative memory involves the conscious recall of personal events, places, and general history.Thus patients with such amnesia remember events before their surgery but fail to recall new events, even with multiple exposures, and must be reintroduced repeatedly to people they meet after the surgery.Second messenger pathways (including G proteins, Ca++/calmodulin-dependent kinase II, protein kinase G, and protein kinase C) are also involved, and these kinases cause protein phosphorylation and changes in the responsiveness of neurotransmitter receptors. A retrograde messenger, perhaps nitric oxide (or carbon monoxide), may be released from postsynaptic neurons to act on presynaptic endings in such a way that transmitter release is enhanced. Immediate-early genes are also activated during LTP. Hence, changes in gene expression may also be involved. With regard to the stages of memory storage, a distinction between short-term memory and long-term memory is useful. Recent events appear to be stored in short-term memory by ongoing neural activity because short-term memory persists for only minutes. Short-term memory is used, for instance, to remember page numbers in a book after looking them up in the index. Long-term memory can be subdivided into an intermediate form, which can be disrupted, and a long-lasting form, which is difficult to disrupt. Memory loss, or amnesia, can be caused by a loss of memory information per se, or it can result from interference with the mechanism for accessing the information. Long-term memory probably involves structural changes because it can remain intact even after events that disrupt short-term memory. The temporal lobes appear to be particularly important for memory because bilateral removal of the hippocampal formation can severely and permanently disrupt recent memory. Short-term and long-term memories are unaffected, but new long-term memories can no longer be established. Thus patients with such amnesia remember events before their surgery but fail to recall new events, even with multiple exposures, and must be reintroduced repeatedly to people they meet after the surgery. This loss of declarative memory involves the conscious recall of personal events, places, and general history.If such patients are given a complex task to perform (e.g., mirror writing), they not only improve during the first training session but also perform better on subsequent days despite their denial of having any earlier experience with that task.The cerebral structures involved in procedural memory are not yet defined.
The problem of determining the cause of a prolonged TIA has been alluded to—many of these cases are a result of emboli.In the original study, unilateral weakness and duration lasting over an hour were most predictive of stroke.Studies subsequent to the original one have given variable sensitivities, for which reason this interesting approach must be considered in clinical context.Although there is little doubt that TIAs are caused by transient focal ischemia, their mechanism is not fully understood. Transient ischemic episodes must be distinguished from other brief neurologic attacks that are from seizures, migraine, and its variants, transient global amnesia, syncope, vertigo from labyrinthine disease, and psychogenic episodes, as emphasized further on. The differentiation of TIAs from other similar transient spells is not always straightforward and occupies considerable attention from neurologists; these distinctions have serious implications with regard to evaluation and treatment. In the clinical analysis of TIAs, it is useful to separate a single transient episode from repeated ones that are all of uniform type. The latter are more a warning of impending vascular occlusion, particularly of the internal carotid artery, whereas the former, especially when prolonged, are again often caused by an embolus that leaves no lasting clinical effect. Prolonged, fluctuating TIAs are the most ominous. Approximately 20 percent of infarcts that follow TIAs occur within a month after the first attack, and approximately 50 percent within a year (Whisnant et al). In an attempt to provide a predictive tool, various scales were devised, among them the “ABCD” system devised by Rothwell and colleagues (2005) and derivatives of this scale. Blood pressure, unilateral weakness, speech disturbance, and the duration of symptoms (all less than 1 h) are added to produce a predictive score for stroke within 1 week. Studies subsequent to the original one have given variable sensitivities, for which reason this interesting approach must be considered in clinical context. In the original study, unilateral weakness and duration lasting over an hour were most predictive of stroke. The problem of determining the cause of a prolonged TIA has been alluded to—many of these cases are a result of emboli.About two-thirds of all patients with TIAs are men with hypertension, reflecting the higher incidence of atherosclerosis in this group.Occasionally, in younger adults, TIAs may occur as relatively benign phenomena, without recognizable features of atherosclerosis or risk factors for it.
Only centrosomes from the father are used in building first and subsequent mitotic spindles.The male centrosome is essential for the alignment of the mitotic spindle that divides chromosomes into the first two cells of the embryo.The resulting zygote contains a diploid (2n) complement of 46 chromosomes and later undergoes the first mitotic division or cleavage.Thus, activation of CatSpers is required for male fertility. Impregnation of the oocyte allows structures lying inside the spermatozoon to enter the cytoplasm of the oocyte. After penetrating the zona pellucida, the spermatozoon enters the perivitelline space between the zona pellucida and the oolemma (oocyte’s plasma membrane). Here, after docking to the oolemma, the spermatozoon plasma membrane fuses with the oolemma. This process, called the impregnation of the oocyte, allows the nucleus of the sperm (containing highly concentrated DNA), the centrosome, the midpiece with the mitochondria, and the kinocilium to be incorporated into the cytoplasm of the oocyte. The tail plasma membrane remains as an appendage to the oolemma. An impregnating spermatozoon generates a molecular signal for resumption and termination of the second meiotic division. This division transforms the secondary oocyte into a mature oocyte and triggers the expulsion of the second polar body into the perivitelline space. The male genetic material lying within the nucleus of incorporated sperm head is unpacked and used for building the male pronucleus, which contains 23 paternal chromosomes. Nuclear membranes of both female and male pronuclei dissolve (without fusion), and the chromosomes align themselves within the common mitotic spindle. The resulting zygote contains a diploid (2n) complement of 46 chromosomes and later undergoes the first mitotic division or cleavage. The male centrosome is essential for the alignment of the mitotic spindle that divides chromosomes into the first two cells of the embryo. Only centrosomes from the father are used in building first and subsequent mitotic spindles.Note that all mitochondria in human cells normally derive from the mother, but all centrosomes originate from the father’s sperm cell.Several spermatozoa may penetrate the zona pellucida, but only one spermatozoon completes the fertilization process.
This view is supported by the finding that the specific antibodies linked to cerebellar degeneration differ from those found in paraneoplastic inflammatory lesions in other parts of the nervous system.Henson and Urich regard the inflammatory changes as an independent process, part of a subacute paraneoplastic encephalomyelitis (see in the following text).These are well emphasized in the series of 47 patients collected by Anderson and colleagues and the 55 cases by Peterson et al, who tabulated these noncerebellar neurologic features. The CSF may show a mild pleocytosis (up to 50 cells/mm3 in a few of our patients) and increased protein, or it may be entirely normal. Early in the course of the disease, CT and MRI show no abnormality, but after a few months, atrophy of the brainstem and cerebellum may appear. In a few cases, T2-weighted MRI discloses increased signal of the cerebellar white matter (Hammack et al), but this has not been uniform in our experience, and furthermore does not correlate well to the presence or degree of Purkinje cell loss (Fig. 30-25). FDG-PET may show hypometabolism in the cerebellum before the MRI changes are detectable. Pathologically, there are diffuse degenerative changes of the cerebellar cortex and deep cerebellar nuclei. Purkinje cells are affected prominently and all parts of the cerebellar cortex are involved. Degenerative changes in the spinal cord, involving the posterior columns and spinocerebellar tracts, have been found rarely. The cerebellar neuronal degeneration is frequently associated with perivascular and meningeal clusters of inflammatory cells. Henson and Urich regard the inflammatory changes as an independent process, part of a subacute paraneoplastic encephalomyelitis (see in the following text). This view is supported by the finding that the specific antibodies linked to cerebellar degeneration differ from those found in paraneoplastic inflammatory lesions in other parts of the nervous system.Antibodies against a nuclear antigen, termed anti-Hu, may also be present; they are more closely linked to the paraneoplastic encephalomyelitis discussed further on.(Hu and Yo are taken from the names of patients in whom the antibody was first found.)
These so-called paraneoplastic disorders are not specific or confined to cancer, but the conditions are linked far more frequently than could be accounted for by chance.In the past 50 years a group of neurologic disorders has been delineated that occur in patients with systemic neoplasia even though the nervous system is not the site of metastases or direct invasion or compression by the tumor.Segmental bibrachial sensory loss has been demonstrated in a few of the cases and a Lhermitte sign (really a symptom) of electric-like sensations down the spine and limbs upon flexing the neck has been reported frequently. The cranial nerve signs most frequently conjoined and indicative of intracranial extension of a foramen magnum tumor are dysphagia, dysphonia, dysarthria, and drooping shoulder (because of vagal, hypoglossal, and spinal accessory involvement); included less often are nystagmus and episodic diplopia, sensory loss over the face and unilateral or bilateral facial weakness, and a Horner syndrome. The clinical course of such lesions often extends for years, with deceptive and unexplained fluctuations. The important diagnostic procedure is contrast-enhanced MRI (Fig. 30-23). With dermoid cysts of the upper cervical region, as in the case reported by Adams and Wegner, complete and prolonged remissions from quadriparesis may occur. Tumors of the foramen magnum, as mentioned, should be differentiated from spinal or brainstem- cerebellar multiple sclerosis, Chiari malformation with syrinx, and bony compression. Persistent occipital neuralgia with a foramen magnum syndrome is particularly suggestive of a tumor at that site. The early occipitonuchal pain must be differentiated from mundane cervical osteoarthritis. Treatment is surgical excision (Hakuba et al) followed by focused radiation if the resection is incomplete and the tumor is known to be radiosensitive. In the past 50 years a group of neurologic disorders has been delineated that occur in patients with systemic neoplasia even though the nervous system is not the site of metastases or direct invasion or compression by the tumor. These so-called paraneoplastic disorders are not specific or confined to cancer, but the conditions are linked far more frequently than could be accounted for by chance.The great variety of clinical presentations of paraneoplastic neurological disease can be appreciated from early series reported by Graus and colleagues of 200 patients: sensory neuropathy, 54 percent; cerebellar ataxia, 10 percent; limbic encephalitis, 9 percent; and others, including multiple sites, in 11 percent.
As noted previously, ECF contains approximately 350 mEq of HCO3 − .Thus HCO3 − minimizes the effect of these strong acids on the pH of ECF.Equation 37.5 Equation 37.6 This neutralization process yields the Na+ salts of the strong acids and removes HCO3 − from the ECF.Nonvolatile acids do not circulate throughout the body but are immediately neutralized by the HCO3 − in ECF.In an individual ingesting a meat-containing diet, dietary intake, cellular metabolism, and fecal HCO3 − loss result in addition of approximately 0.7 to 1.0 mEq/kg body weight of nonvolatile acid to the body each day (50–100 mEq/day for most adults). This acid, referred to as net endogenous acid production (NEAP), results in an equivalent loss of HCO3 − from the body that must be replaced. Wheninsulinlevelsarenormal,carbohydratesandfatsarecompletelymetabolizedtoCO2+ H2O.However,ifinsulinlevelsareabnormallylow(e.g.,diabetesmellitus),cellularmetabolismleadstoproductionofseveralorganicketoacids(e.g.,β-hydroxybutyricacidandacetoaceticacidfromfattyacids). IntheabsenceofadequatelevelsofO2(hypoxia),anaerobicmetabolismbycellscanalsoleadtoproductionoforganicacids(e.g.,lacticacid)ratherthanCO2+ H2O.Thisfrequentlyoccursinnormalindividualsduringvigorousexercise.Poortissueperfusion,suchasoccurswithreducedcardiacoutput,canalsoleadtoanaerobicmetabolismbycellsandthustoacidosis.IntheseconditionstheorganicacidsaccumulateandthepHofbodyfluidsdecreases(acidosis).Treatment(e.g.,administrationofinsulininthecaseofdiabetes)orimproveddeliveryofadequatelevelsofO2totissues(e.g.,inthecaseofpoortissueperfusion)resultsinthemetabolismoftheseorganicacidstoCO2+ H2O,whichconsumesH+ andtherebyhelpscorrecttheacid-basedisorder. Nonvolatile acids do not circulate throughout the body but are immediately neutralized by the HCO3 − in ECF. Equation 37.5 Equation 37.6 This neutralization process yields the Na+ salts of the strong acids and removes HCO3 − from the ECF. Thus HCO3 − minimizes the effect of these strong acids on the pH of ECF. As noted previously, ECF contains approximately 350 mEq of HCO3 − .To maintain acid-base balance the kidneys must replenish the HCO3 − lost by neutralization of the nonvolatile acids, a process termed renal net acid excretion (RNAE).Net Acid Excretion by the Kidneys Under steady-state conditions, NEAP must equal RNAE to maintain acid-base balance.Although NEAP varies from individual to individual and from day to day in anyone individual, it is not regulated.
The EEG is the most sensitive, indeed indispensable, tool for the diagnosis of epilepsy; but like other ancillary tests, it must be used in conjunction with clinical data.The EEG provides confirmation of Hughlings Jackson’s concept of epilepsy—that it represents a recurrent, sudden, excessive discharge of cortical neurons.2 and earlier in this chapter.The spike-and-wave complex, which represents brief excitation followed by slow-wave inhibition, is the type of EEG pattern that characterizes the clonic (inhibitory) phase of the focal motor or grand mal seizure. By contrast, this strong element of inhibition is present diffusely throughout an “absence” attack, a feature that perhaps accounts for the failure of excitation to spread to lower brainstem and spinal structures (tonic-clonic movements do not occur). Earlier mentioned is the work by Blumenfeld’s group, suggesting that the interruption of consciousness in this syndrome can be linked with electrophysiologic changes in the thalamus, comparable to what is described for types of generalized seizure. Of theoretical importance is the observation that a seizure focus may establish, via commissural connections, a persistent secondary focus in the corresponding cortical area of the opposite hemisphere (mirror focus). The nature of this phenomenon is obscure; it may be similar to the “kindling” phenomenon mentioned earlier in animals, where a repeated nonconvulsive electrical stimulation of normal cortex induces a permanent epileptic focus. No morphologic change is visible in the mirror focus, at least by light microscopy. The mirror focus may be a source of confusion when trying to identify the side of the primary discharging lesion by EEG. However, there is only limited evidence that mirror foci related to the kindling phenomenon produce seizures in humans (see Goldensohn). The origins of EEG activity of an epileptic focus and the generalization of seizures are discussed in Chap. 2 and earlier in this chapter. The EEG provides confirmation of Hughlings Jackson’s concept of epilepsy—that it represents a recurrent, sudden, excessive discharge of cortical neurons. The EEG is the most sensitive, indeed indispensable, tool for the diagnosis of epilepsy; but like other ancillary tests, it must be used in conjunction with clinical data.By contrast, a proportion of epileptic patients have a perfectly normal interictal EEG.Using standard methods of scalp recording, the EEG may even be normal during the experiential aura of a simple or complex partial seizure.
Patients with panic disorder have a heightened sensitivity to somatic symptoms, which triggers increasing arousal, setting off the panic attack; accordingly, therapeutic intervention involves altering the patient’s cognitive interpretation of anxiety-producing experiences as well as preventing the attack itself.Agents that block serotonin reuptake can prevent attacks.Electrocardiogram (ECG) and echocardiogram may detect some cardiovascular conditions associated with panic such as paroxysmal atrial tachycardia and mitral valve prolapse. In two studies, panic disorder was the primary diagnosis in 43% of patients with chest pain who had normal coronary angiograms and was present in 9% of all outpatients referred for cardiac evaluation. Panic disorder has also been diagnosed in many patients referred for pulmonary function testing or with symptoms of irritable bowel syndrome. Etiology and Pathophysiology The etiology of panic disorder is unknown but appears to involve a genetic predisposition, altered autonomic responsivity, and social learning. Panic disorder shows familial aggregation; the disorder is concordant in 30–45% of monozygotic twins, and genome-wide screens have identified suggestive risk loci. Acute panic attacks appear to be associated with increased noradrenergic discharges in the locus coeruleus. Intravenous infusion of sodium lactate evokes an attack in two-thirds of panic disorder patients, as do the α2-adrenergic antagonist yohimbine, cholecystokinin tetrapeptide (CCK-4), and carbon dioxide inhalation. It is hypothesized that each of these stimuli activates a pathway involving noradrenergic neurons in the locus coeruleus and serotonergic neurons in the dorsal raphe. Agents that block serotonin reuptake can prevent attacks. Patients with panic disorder have a heightened sensitivity to somatic symptoms, which triggers increasing arousal, setting off the panic attack; accordingly, therapeutic intervention involves altering the patient’s cognitive interpretation of anxiety-producing experiences as well as preventing the attack itself.The cornerstone of drug therapy is antidepressant medication (Tables 466-1 through 466-3).Selective serotonin reuptake inhibitors (SSRIs) benefit the majority of panic disorder patients and do not have the adverse effects of tricyclic antidepressants (TCAs).
Individuals with acute stress dis- behavior with little provocation.It is very common for individuals with acute stress disorder to experience problems with sleep onset and maintenance, which may be associated with nightmares or with gen- eralized elevated arousal that prevents adequate sleep.The triggering cue could be a physical sensation (e.g., a sense of heat for a burn victim, diz- ziness for survivors of head trauma), particularly for individuals with highly somatic pre- sentations. The individual may have a persistent inability to feel positive emotions (e.g., happiness, joy, satisfaction, or emotions associated with intimacy, tenderness, or sexual- ity) but can experience negative emotions such as fear, sadness, anger, guilt, or shame. Alterations in awareness can include depersonalization, a detached sense of oneself (e.g., seeing oneself from the other side of the room), or derealization, having a distorted view of one’s surroundings (e.g., perceiving that things are moving in slow motion, seeing things in a daze, not being aware of events that one would normally encode). Some individuals also report an inability to remember an important aspect of the traumatic event that was presumably encoded. This symptom is attributable to dissociative amnesia and is not at- tributable to head injury, alcohol, or drugs. Stimuli associated with the trauma are persistently avoided. The individual may refuse to discuss the traumatic experience or may engage in avoidance strategies to minimize awareness of emotional reactions (e.g., excessive alcohol use when reminded of the ex- perience). This behavioral avoidance may include avoiding watching news coverage of the traumatic experience, refusing to return to a workplace where the trauma occurred, or avoiding interacting with others who shared the same traumatic experience. It is very common for individuals with acute stress disorder to experience problems with sleep onset and maintenance, which may be associated with nightmares or with gen- eralized elevated arousal that prevents adequate sleep. Individuals with acute stress dis- behavior with little provocation.Concentration difficulties, including difficulty remembering daily events (e.g., forgetting one’s telephone number) or attending to focused tasks (e.g., following a conversation for a sustained period of time), are commonly reported.
Note that the arterial inflow for the debranched visceral arteries comes from the left common iliac artery.Table 22-4Classification of and common treatment strategies for endoleakType I• Incomplete seal between stent graft and aorta at the proximal landing site (Type Ia), the distal landing site (Type Ib), or branch module, fenestration, or plug (Type Ic)• Early reintervention to improve seal or conversion to open surgeryType II• Retrograde perfusion of sac from excluded collateral arteries• Surveillance; as-needed occlusion with percutaneous or other interventionsType III• Incomplete seal between overlapping stent graft or module (Type IIIa), or tear in graft fabric (Type IIIb)• Early reintervention to cover or conversion to open surgeryType IV• Perfusion of sac due to porosity of material• Surveillance; as-needed reintervention to reline stent graftType V• Expansion of sac with no identifiable source• Surveillance; as-needed reintervention to reline stent graftmindful of spinal cord perfusion and avoid periods of relative hypotension while maintaining these low pressures.Endovascular Procedures Many of the complications are directly related to manipulation of the delivery system within the iliac arteries and aorta.146 Patients with small, calcified, tor-tuous iliofemoral arteries are at particularly high risk for life-threatening iliac artery rupture. Although relatively uncommon, acute iatrogenic retrograde dissection into the aortic arch and ascending aorta is a life-threatening complication that neces-sitates emergency repair of the ascending aorta and aortic arch via sternotomy and cardiopulmonary bypass.109 The most important risk factors for this complication include incautious wire and catheter manipulation, aggressive proximal ballooning (especially in cases of acute descending thoracic aortic dissection), and hybrid arch repair in which the native ascending aorta is dilated (more than 4 cm).Of note, ret-rograde aortic dissection may also occur several months after initial repair.147Another significant complication of descending thoracic aortic stent grafting is endoleak.An endoleak occurs when there is a persistent flow of blood (visible on radiologic imaging) into the aneurysm sac, and it may occur during the initial proce-dure or develop over time.
403-5).Surgical resection of GH-secreting adenomas is the initial treatment for most patients (Fig.The goal of treatment is to control GH and IGF-I hypersecretion, ablate or arrest tumor growth, ameliorate comorbidities, restore mortality rates to normal, and preserve pituitary function.Acromegaly is associated with an increased risk of colon polyps and mortality from colonic malignancy; polyps are diagnosed in up to one-third of patients. Overall mortality is increased about threefold and is due primarily to cardiovascular and cerebrovascular disorders and respiratory disease. Unless GH levels are controlled, survival is reduced by an average of 10 years compared with an age-matched control population. Laboratory Investigation Age-matched serum IGF-I levels are elevated in acromegaly. Consequently, an IGF-I level provides a useful laboratory screening measure when clinical features raise the possibility of acromegaly. Due to the pulsatility of GH secretion, measurement of a single random GH level is not useful for the diagnosis or exclusion of acromegaly and does not correlate with disease severity. The diagnosis of acromegaly is confirmed by demonstrating the failure of GH suppression to <0.4 μg/L within 1–2 h of an oral glucose load (75 g). When newer ultrasensitive GH assays are used, normal nadir GH levels are even lower (<0.05 μg/L). About 20% of patients exhibit a paradoxical GH rise after glucose. PRL should be measured, as it is elevated in ~25% of patients with acromegaly. Thyroid function, gonadotropins, and sex steroids may be attenuated because of tumor mass effects. Because most patients will undergo surgery with glucocorticoid coverage, tests of ACTH reserve in asymptomatic patients are more efficiently deferred until after surgery. The goal of treatment is to control GH and IGF-I hypersecretion, ablate or arrest tumor growth, ameliorate comorbidities, restore mortality rates to normal, and preserve pituitary function. Surgical resection of GH-secreting adenomas is the initial treatment for most patients (Fig. 403-5).Irradiation or repeat surgery may be required for patients who cannot tolerate or do not respond to adjunctive medical therapy.The high rate of late hypopituitarism and the slow rate (5–15 years) of biochemical response are the FIGURE 403-4 Features of acromegaly/gigantism.A 22-year-old man with gigantism due to excess growth hormone is shown to the left of his identical twin.
Repeat endoscopies are often necessary to document efficacy of these eliminations.common causative dietary antigens.Linear furrowing is also seen.White plaques on the surface are collections of eosinophils (eosinophilic abscesses).May help reflux symptoms Abstaining from caffeine Inexpensive, offers some benefit Positional therapy—upright in seat, elevate Prone positioning with head of crib or bed up is helpful, but not for young infants because of risk of SIDS Weight loss when indicated Increased weight (especially abdominal) increases intra-abdominal pressure, leading to reflux H2 receptor antagonist Reduces heartburn, less effective for healing esophagitis Metoclopramide Enhances stomach emptying and LES tone. Real benefit is often minimal Feeding jejunostomy Useful in child requiring tube feeds. Delivering feeds downstream eliminates GERD GERD, Gastroesophageal reflux disease; LES, lower esophageal sphincter; SIDS, sudden infant death syndrome. Figure 128-1 Histologic image of eosinophilic esophagitis. Note the large number of eosinophils within the lamina propria. a food impaction in an acutely symptomatic patient or esophageal stricture in someone with chronic disease. Exposure to identified causative antigens needs to be eliminated. Identification can be difficult, as typical allergy testing (skin prick, RAST, and immunocap assays) only identifies IgE-mediated antigens. Atopic patch testing may be more reliable but is not standardized and can be difficult to perform. One approach is to eliminate cow’s milk, soy, wheat, eggs, peanuts, and fish/shellfish from the diet, as these are the most Figure 128-2 Endoscopic picture of eosinophilic esophagi-tis. White plaques on the surface are collections of eosinophils (eosinophilic abscesses). Linear furrowing is also seen. common causative dietary antigens. Repeat endoscopies are often necessary to document efficacy of these eliminations.Systemic glucocorticoids can decrease symptoms, but longterm use is discouraged secondary to complications.
In surviving cells, simple defects may be reparable by various enzyme repair systems contained in mammalian cells (see Chapter 6).Ionizing radiation can cause many types of damage in DNA, including single-base damage, singleand double-strand breaks, and crosslinks between DNA and protein.However, as discussed in Chapter 6, in dividing cells DNA damage is detected by sensors that produce signals leading to the upregulation of p53, the “guardian of the genome.” p53 in turn upregulates the expression of genes that initially lead to cell-cycle arrest and, if the DNA damage is too great to repair, genes that cause cell death through apoptosis. Understandably, therefore, tissues with a high rate of cell turnover, such as gonads, bone marrow, lymphoid tissue, and the mucosa of the GI tract, are extremely vulnerable to radiation, and the injury is manifested early after exposure. http://ebooksmedicine.net Hypoxia. The production of ROS by the radiolysis of water is the most important mechanism of DNA damage by ionizing radiation. Tissue hypoxia, such as may exist in the center of rapidly growing, poorly vascularized tumors, may thus reduce the extent of damage and the effectiveness of radiotherapy directed against tumors. Vascular damage. Damage to endothelial cells, which are moderately sensitive to radiation, may cause narrowing or occlusion of blood vessels, leading to impaired healing, fibrosis, and chronic ischemic atrophy. These changes may appear months or years after exposure. Despite the low sensitivity of brain cells to radiation, vascular damage after irradiation can lead to late manifestations of radiation injury in this tissue. The most important cellular target of ionizing radiation is DNA ( Fig. 8.14 ). Damage to DNA caused by ionizing radiation that is not precisely repaired leads to mutations, which can manifest years or decades later as cancer. Ionizing radiation can cause many types of damage in DNA, including single-base damage, singleand double-strand breaks, and crosslinks between DNA and protein. In surviving cells, simple defects may be reparable by various enzyme repair systems contained in mammalian cells (see Chapter 6).However, double-strand breaks may persist without repair, or the repair of lesions may be imprecise (error prone), creating mutations.
Predictors of SVR include viral factors, as well as patient factors.For patients receiving PEG-IFN-a/RBV regimens, which are associated with many side effects and poor response, clinical decisions of whether to initiate therapy are largely based on likelihood of SVR.Type III IFNs share many therapeutic effects with type I IFNs, eg, IFN-a (Chapter 55), such as being directly induced by viruses and acting through JAK-STAT signal transduction pathways (via distinct heterodimeric receptor signaling complexes) to produce antiviral activity in cells. Type III IFNs play a role in hepatitis C virus (HCV) infection. Genetic variants near the IFNL3 gene were found to be most significantly associated with HCV treatment response to pegylated-IFN-a (PEG-IFN-a), in combination with ribavirin (RBV). Approximately twofold greater cure rates were observed in patients with a favorable genotype. While the mechanism underlying this association has yet to be fully elucidated, the rs12979860 variant near IFNL3 is considered the strongest baseline predictor of a cure for patients with HCV-1 receiving PEG-IFN-a/RBV. The favorable allele, the rs12979860 variant, is inherited most frequently in Asians (∼90%), and least frequently in Africans (Table 5–1). This frequency distribution is remarkably similar to rates of response to HCV PEG-IFN-a/RBV treatment among the three ethnic groups. Pegylated interferon with ribavirin: Chronic HCV affects 160 million people worldwide and is a leading cause of cirrhosis of the liver and liver cancer. The goal for HCV antiviral therapy is to resolve the infection, defined clinically as achievement of sustained virologic response (SVR), ie, undetectable HCV RNA measured 6 months after finishing treatment. For patients receiving PEG-IFN-a/RBV regimens, which are associated with many side effects and poor response, clinical decisions of whether to initiate therapy are largely based on likelihood of SVR. Predictors of SVR include viral factors, as well as patient factors.Guidelines according to CPIC are shown in Table 5–2.In the above examples, variations within single gene loci are described that are significantly associated with altered drug response or toxicity.However, it is expected that polygenic influences, ie, the combinatorial effect of multiple genes on drug response, may more accurately describe individual differences with respect to clinical outcomes.
Of course, many variations are possible.Coagulopathy also can worsen because of these byproducts as well as fibrinolysis.The arterial anastomosis between the donor common hepatic or celiac trunk is most often performed with the recipi-ent CHA in an end-to-end fashion.The ligamentous attachments of the liver are dissected free. The vascular structures are isolated, including the suprahepatic and infrahepatic vena cava, the portal vein, and hepatic artery (Fig. 11-15). The bile duct, portal structures, and vena cava are divided, completing the hepatectomy (Fig. 11-16)—often the bloodiest and most difficult part of the operation, particularly in the presence of extensive varices and severe coagulopathy.After the liver is removed, the anhepatic phase begins. This phase is characterized by the absence of inferior vena caval return to the heart and by portal congestion due to clamp-ing of the portal vein. Significant hemodynamic instability and increased variceal bleeding can occur. Patients who are unable to tolerate this phase can be placed on venovenous bypass, with cannulas drawing blood from the IVC via the femoral vein and via the portal vein, returning it to the systemic circulation via the subclavian vein. Venovenous bypass itself can cause complica-tions, including air embolism, thromboembolism, and trauma to the cannulated vessels.Figure 11-15. Cirrhotic liver immobilized in preparation for com-plete hepatectomy.Figure 11-16. Isolation and division of the hilar structures to dis-eased liver-hepatic artery, portal vein, and common bile duct.The donor liver is placed in the orthotopic position. The suprahepatic vena caval anastomosis is performed first in an end-to-end fashion, followed by the infrahepatic vena caval and portal anastomosis, both also end-to-end. The liver is then reper-fused, often leading to a period of hemodynamic instability and cardiac arrhythmias due to the release of byproducts of ischemia from the donor liver. Coagulopathy also can worsen because of these byproducts as well as fibrinolysis.The arterial anastomosis between the donor common hepatic or celiac trunk is most often performed with the recipi-ent CHA in an end-to-end fashion. Of course, many variations are possible.If necessary for technical reasons, the recipient common duct can be joined to a Roux-en-Y limb.Some surgeons choose to insert a T-tube or place internal stents in the common bile duct to protect the anastomosis.The piggyback technique is a common variation of the standard technique.The recipient’s IVC is preserved by care-fully dissecting off the posterior aspect of the liver.
Patients with HIV infection often have an indolent course that presents as mild exercise intolerance or chest tightness without fever or cough and a normal or nearly normal posterior-anterior chest radiograph, with progression over days, weeks, or even a few months to fever, cough, diffuse alveolar infiltrates, and profound hypoxemia.Untreated, PCP is invariably fatal.The organisms are identified with the specific stains indicated above for lung biopsy. While expectorated sputum or throat swabs have very low sensitivity, an induced sputum sample obtained and interpreted by an experienced provider can be highly sensitive and specific. The reported sensitivity of induced sputum for PCP is widely variable (55–90%), however, and is dependent on both the characteristics of the patient and the experience of the center conducting the test. Recently, many laboratories have offered polymerase chain reaction (PCR) testing of respiratory specimens for Pneumocystis. However, these PCR tests are so sensitive that it is difficult to distinguish patients with colonization (i.e., those whose acute lung disease is due to some other process but who have low levels of Pneumocystis DNA in the lungs) from those with acute pneumonia due to Pneumocystis. Such PCR tests on appropriate samples may be more useful for ruling out a diagnosis of PCP if they are negative than for definitively attributing the disease to Pneumocystis. There has been considerable interest in serologic tests such as assays for (1→3)-β-D-glucan, levels of which are frequently elevated in patients with PCP. However, no serologic assays developed to date offer substantial sensitivity or specificity. Untreated, PCP is invariably fatal. Patients with HIV infection often have an indolent course that presents as mild exercise intolerance or chest tightness without fever or cough and a normal or nearly normal posterior-anterior chest radiograph, with progression over days, weeks, or even a few months to fever, cough, diffuse alveolar infiltrates, and profound hypoxemia.Rare patients also develop distributive shock.A few unusual patients present with extrapulmonary manifestations in the skin or soft tissue, retina, brain, liver, kidney, or spleen that are nonspecific in presentation and can be diagnosed only by histology.
bFluorescence in-situ (FISH) is typically performed for chromosomes 21, 18, 13, X, and Y. PCR = polymerase chain reaction.When performing the procedure in a diamnionic twin gestation, careful attention is paid to the aThe volume of fluid needed for each test may vary according to individual laboratory specifications.Multifetal Pregnancy.15, p. 305).Discomfort from the procedure is considered minor, and local anesthetic has not been found to be beneicial (Mujezinovic, 2011). Following the procedure, the color and clarity of the luid are documented. Amnionic fluid should be clear and colorless or pale yellow. Blood-tinged luid is more frequent if there is transplacental passage of the needle. However, it generally clears with continued aspiration. The placenta implants along the anterior uterine wall in approximately half of pregnancies. In these cases, the placenta will be traversed by the needle approximately 60 percent of the time (Bombard, 1995). Needle passage through the placenta is avoided when possible, although fortunately this has not been associated with greater pregnancy loss rates (Marthin, 1997). Dark brown or greenish luid may represent a past episode of intraamnionic bleeding. he volume of fluid generally needed for commonly performed analyses is shown in Table 14-12. Because the initial 1 to 2 mL of fluid aspirate may be contaminated with maternal cells, it is generally discarded. Approximately 20 to 30 mL of fluid is then collected for either fetal CMA or karyotyping before removing the needle. Sonography is used to observe the uterine puncture site for bleeding, and fetal cardiac motion is documented at the procedure's end. If the patient is h D-negative and unsensitized, anti-D immune globulin is administered following the procedure (Chap. 15, p. 305). Multifetal Pregnancy. When performing the procedure in a diamnionic twin gestation, careful attention is paid to the aThe volume of fluid needed for each test may vary according to individual laboratory specifications. bFluorescence in-situ (FISH) is typically performed for chromosomes 21, 18, 13, X, and Y. PCR = polymerase chain reaction.Until recently, a small quantity of dilute indigo carmine dye was often injected before removing the needle from the irst sac, with return of clear amnionic fluid anticipated following needle placement into the second sac.Because of widespread shortages of indigo carmine dye, most experienced providers ofer amniocentesis in multifetal gestations when indicated, without dye injection.
Posterior to the mandibular symphysis on the internal surface of the mandible are two pairs of small spines, one pair immediately above the other pair.8.249B).8.249B), which anchors the lower teeth, and on its external surface on each side is a small mental foramen (Fig.The upper surface of the body of the mandible bears the alveolar arch (Fig.Cartilaginous part of the pharyngotympanic tube The trumpet-shaped cartilaginous part of the pharyngotympanic tube is in a groove between the anterior margin of the petrous part of the temporal bone and the posterior margin of the greater wing of the sphenoid (Fig. 8.248A). The medial and lateral walls of the cartilaginous part of the pharyngotympanic tube are formed mainly of cartilage, whereas the more inferolateral wall is more fibrous and is known as the membranous lamina. The apex of the cartilaginous part of the pharyngotympanic tube connects laterally to the opening of the bony part in the temporal bone. The expanded medial end of the cartilaginous part of the pharyngotympanic tube is immediately posterior to the upper margin of the medial plate of the pterygoid process and opens into the nasopharynx. The cartilaginous part of the pharyngotympanic tube is lateral to the attachment of the levator veli palatini muscle and medial to the spine of the sphenoid. The tensor veli palatini muscle is attached, in part, to the membranous lamina. The mandible is the bone of the lower jaw (Fig. 8.249). It consists of a body of right and left parts, which are fused anteriorly in the midline (mandibular symphysis), and two rami. The site of fusion is particularly visible on the external surface of the bone as a small vertical ridge in the midline. The upper surface of the body of the mandible bears the alveolar arch (Fig. 8.249B), which anchors the lower teeth, and on its external surface on each side is a small mental foramen (Fig. 8.249B). Posterior to the mandibular symphysis on the internal surface of the mandible are two pairs of small spines, one pair immediately above the other pair.8.249A,C), and are attachment sites for a pair of muscles that pass into the tongue and a pair of muscles that connect the mandible to the hyoid bone.Extending from the midline and originating inferior to the mental spines is a raised line or ridge (the mylohyoid line) (Fig.
The plasma membrane therefore has a highly asymmetric phospholipid composition, which is actively maintained by the flip-pases (see Figure 10–15).The two other major membrane phospholipids—phosphatidylethanolamine and phosphatidylserine (see Figure 10–3)—as well as the minor phospholipid phosphatidylinositol (PI), are all synthesized in this way. Because phospholipid synthesis takes place in the cytosolic leaflet of the ER lipid bilayer, there needs to be a mechanism that transfers some of the newly formed phospholipid molecules to the lumenal leaflet of the bilayer. In synthetic lipid bilayers, lipids do not “flip-flop” in this way (see Figure 10–10). In the ER, however, phospholipids equilibrate across the membrane within minutes, which is almost 100,000 times faster than can be accounted for by spontaneous “flipflop.” This rapid trans-bilayer movement is mediated by a poorly characterized asymmetric lipid bilayer of plasma membrane phospholipid translocator called a scramblase, which nonselectively equilibrates phospholipids between the two leaflets of the lipid bilayer (Figure 12–54). Thus, the different types of phospholipids are thought to be equally distributed between the two leaflets of the ER membrane. The plasma membrane contains a different type of phospholipid translocator that belongs to the family of P-type pumps (discussed in Chapter 11). These flip-pases specifically recognize those phospholipids that contain free amino groups in their head groups (phosphatidylserine and phosphatidylethanolamine—see Figure 10–3) and transfers them from the extracellular to the cytosolic leaflet, using the energy of ATP hydrolysis. The plasma membrane therefore has a highly asymmetric phospholipid composition, which is actively maintained by the flip-pases (see Figure 10–15).The ER also produces cholesterol and ceramide (Figure 12–55).Ceramide is made by condensing the amino acid serine with a fatty acid to form the amino alcohol sphingosine (see Figure 10–3); a second fatty acid is then covalently added to form ceramide.
The typical symptom is a diffuse mass in the neck, which may be managed medically or may need surgical excision if the mass is large enough to affect the patient’s life or cause respiratory problems.Most patients are euthyroid (i.e., have normal serum thyroxine levels).Ectopic thyroid tissue is relatively rare. More frequently seen is the cystic change that arises from the thyroglossal duct. The usual symptom of a thyroglossal duct cyst is a midline mass. Ultrasound easily demonstrates its nature and position, and treatment is by surgical excision. The whole of the duct as well as a small part of the anterior aspect of the hyoid bone must be excised to prevent recurrence. In the clinic A thyroidectomy is a common surgical procedure. In most cases it involves excision of part or most of the thyroid gland. This surgical procedure is usually carried out for benign diseases, such as multinodular goiter and thyroid cancer. Given the location of the thyroid gland, there is a possibility of damaging other structures when carrying out a thyroidectomy, namely the parathyroid glands and the recurrent laryngeal nerve (Fig. 8.181). Assessment of the vocal folds is necessary before and after thyroid surgery because the recurrent laryngeal nerves are closely related to ligaments that bind the gland to the larynx and can be easily traumatized during surgical procedures. In the clinic Thyroid gland pathology is extremely complex. In essence, thyroid gland pathology should be assessed from two points of view. First, the thyroid gland may be diffusely or focally enlarged, for which there are numerous causes. Second, the thyroid gland may undersecrete or oversecrete the hormone thyroxine. One of the commonest disorders of the thyroid gland is a multinodular goiter, which is a diffuse irregular enlargement of the thyroid gland with areas of thyroid hypertrophy and colloid cyst formation. Most patients are euthyroid (i.e., have normal serum thyroxine levels). The typical symptom is a diffuse mass in the neck, which may be managed medically or may need surgical excision if the mass is large enough to affect the patient’s life or cause respiratory problems.Isolated tumors may or may not secrete thyroxine depending on their cellular morphology.Treatment is usually by excision.Immunological diseases may affect the thyroid gland and may overstimulate it to produce excessive thyroxine.These diseases may be associated with other extrathyroid manifestations, which include exophthalmos, pretibial myxedema, and nail changes.
Similarly, there is an association between a long lactation of 12 to 23 months (cumulative lactation of all pregnancies) and a significant reduction of hypertension, hyperlipidemia, cardiovascular disease, and diabetes in the mother.Decreased risk of postpartum hemorrhages, more rapid uterine involution, longer period of amenorrhea, and decreased postpartum depression have been observed.Pediatric health care providers should approach breastfeeding at multiple levels (individual, community, social, and political) to reach the goals of “Healthy People in 2020”; its targets include 82% of infants with any breastfeeding, 23.7% of infants with exclusive breastfeeding for the first 6 months of life, and lactation support at work of 38%. In collaboration with national and global organizations, including the AAP, World Health Organization (WHO), UNICEF, the Centers for Disease Control and Prevention (CDC), and the Joint Commission, hospitals are asked to promote and facilitate breastfeeding. The first 2 days of breastfeeding, and perhaps the first hour of life, may determine the success of breastfeeding. The current rate of breastfeeding initiation for the total U.S. population is 75% (Figure 27-1). There is greater emphasis to improve and standardize hospital practices with “Baby Friendly” programs for breastfeeding support. The Department of Health and Human Services and theCDC recognize that breastfeeding offers infants, mothers,and society compelling advantages in industrialized and developing countries. Human milk feeding decreases the incidence and severity of diarrhea, respiratory illnesses, otitis media, bacteremia, bacterial meningitis, and necrotizingenterocolitis. There are beneficial effects of feeding preterm infants with human milk on long-term neurodevelopment (IQ) in preterm infants. Preterm breastfed infants also have a lower readmission rate in the first year of life. Mothers who breastfeed experience both shortand longterm health benefits. Decreased risk of postpartum hemorrhages, more rapid uterine involution, longer period of amenorrhea, and decreased postpartum depression have been observed. Similarly, there is an association between a long lactation of 12 to 23 months (cumulative lactation of all pregnancies) and a significant reduction of hypertension, hyperlipidemia, cardiovascular disease, and diabetes in the mother.Adequacy of milk intake can be assessed by voidingand stooling patterns of the infant.A well-hydrated infantvoids six to eight times a day.Each voiding should soak, notmerely moisten, a diaper, and urine should be colorless.By5 to 7 days, loose yellow stools should be passed at least fourtimes a day.Rate of weight gain provides the most objectiveindicator of adequate milk intake.
Finally, still others have demonstrated that levels of the placental antithrombotic molecule— annexin V—are reduced within the placental villa from those women with recurrent pregnancy loss who are antiphospholipid antibody positive (267).Others noted rapid development of atherosclerosis in the decidual spiral arteries of patients who test positive for antiphospholipid antibodies (266).In a large series of couples with recurrent abortion, the incidence of the antiphospholipid syndrome was between 3% and 5% (112). The presence of anticardiolipin antibodies among patients with known systemic lupus erythematosus portends less favorable pregnancy outcomes (255). A number of mechanisms have been proposed by which antiphospholipid antibodies might mediate pregnancy loss (256). Antibodies against phospholipids could increase thromboxane and decrease prostacyclin synthesis within placental vessels. The resultant prothrombotic environment could promote vascular constriction, platelet adhesion, and placental infarction (257–259). Alternatively, in vitro evidence from trophoblast cell lines indicates that IgM action against phosphatidylserine inhibits formation of syncytial trophoblast (260). Syncytialization is required for proper placental function. One study demonstrated that both extravillous cytotrophoblast and syncytiotrophoblast cells synthesize β2 glycoprotein-1, the essential cofactor for antiphospholipid antibody binding (261). Although it gives insight into pathophysiology, the prognostic value of serum levels of specific antibodies against β2 glycoprotein-1 with respect to pregnancy outcome among recurrent pregnancy loss patients is contentious and may be poorer than that of standard anticardiolipin antibodies (262–264). Some have proposed that sera from antibody positive recurrent pregnancy loss patients is particularly adept at inhibiting trophoblast adhesion to endothelial cells in vitro (265). Others noted rapid development of atherosclerosis in the decidual spiral arteries of patients who test positive for antiphospholipid antibodies (266). Finally, still others have demonstrated that levels of the placental antithrombotic molecule— annexin V—are reduced within the placental villa from those women with recurrent pregnancy loss who are antiphospholipid antibody positive (267).The characteristic lesions for this syndrome (placental infarction, abruption, and hemorrhage) are typically missing in women with antiphospholipid antibodies, and these same pathologic lesions can be found in placentae from women with recurrent abortion who do not have biochemical evidence of antiphospholipid antibodies (256,268–270).
The presence of vulvar symptoms such as itching or burning may prompt a patient to seek care; however, this anatomic site is not one that is easily inspected by the patient.The possibility of sexual abuse, incest, or involuntary intercourse should be considered for young adolescents with vulvovaginal symptoms, STDs, or pregnancy.14.10).Various developmental anomalies—vaginal agenesis, imperforate hymen, transverse and longitudinal vaginal septa, vaginal and uterine duplications, hymenal bands, and septa—most frequently are diagnosed in early adolescents with amenorrhea (for the obstructing abnormalities) or with concerns such as inability to use tampons (for hymenal and vaginal bands and septa). These developmental abnormalities must be evaluated carefully to determine both external and internal anatomy. Figure 14.16 Hymenal band. A tight hymenal ring may be discovered when the patient seeks care because of concerns about the inability to use tampons or have intercourse. Both manual dilation and small relaxing incisions at 6 o’clock and 8 o’clock in the hymenal ring can be effective. This procedure can sometimes be done in the office using local anesthesia but may require conduction or general anesthesia in the operating room. Hymenal bands are not rare and lead to difficulty in using tampons; they usually can be incised in the office using local anesthetic (Fig. 14.16). Hypertrophy of the labia minora may be considered a variant of normal, and reassurance rather than a cosmetic surgical reduction is appropriate as the primary therapy. Surgical management is described, although the procedure could be considered to be esthetic rather than medically mandated. Genital ulcerations may occur in girls with leukemia or other cancers requiring chemotherapy (129,130). Vulvar ulcerations in the absence of sexual activity or infectious etiology are described as vulvar aphthosis (46) (Fig. 14.10). The possibility of sexual abuse, incest, or involuntary intercourse should be considered for young adolescents with vulvovaginal symptoms, STDs, or pregnancy. The presence of vulvar symptoms such as itching or burning may prompt a patient to seek care; however, this anatomic site is not one that is easily inspected by the patient.Vulvar self-examination should be encouraged and could potentially result in the earlier diagnosis of vulvar lesions such as melanoma.Adolescents presenting with vulvar itching may have lichen sclerosus; this condition can be relatively asymptomatic, even when an examination reveals loss of anatomic structures and scarring (11) (Fig.14.4).
AJCC Cancer Staging Manual, 8th Ed.(Eds.)Amin MB, Edge SB, Greene FL, et al.T1bTumor >1 cm but ≤2 cm in greatest dimension T1cTumor >2 cm but ≤3 cm in greatest dimensionT2Tumor >3 cm but ≤5 cm or having any of the following features:• Involves the main bronchus regardless of distance to the carina, but without involvement of the carina• Invades visceral pleura (PL1 or PL2)• Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lungT2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.Brunicardi_Ch19_p0661-p0750.indd 69001/03/19 7:01 PM CHAPTER 19691CHEST WALL, LUNG, MEDIASTINUM, AND PLEURATable 19-11cStage Group in the 8th AJCC Tumor, Node, Metastasis staging systemN0N1N2N3T1/M0T1aIA1IIBIIIAIIIBT1bIA2IIBIIIAIIIBT1cIA3IIBIIIAIIIBT2/M0T2aIBIIBIIIAIIIBT2bIIAIIBIIIAIIIBT3/M0IIBIIIAIIIBIIICT4/M0IIIAIIIAIIIBIIICTX/M1M1aIVAIVAIVAIVAM1bIVAIVAIVAIVAM1cIVBIVBIVBIVBUsed with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed.Most pleural (pericardial) effusions with lung cancer are a result of the tumor.In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate.If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
Atypical HUS is caused by acquired or hereditary abnormalities of factors that dampen activation of complement by the alternative pathway.All of these alterations may contribute to the formation of thrombi, which tend to be most prominent in glomerular capillaries, afferent arterioles, and interlobular arteries.At high doses, the toxin causes endothelial cell death.In the primary forms of thrombotic microangiopathies, the etiology is well-defined ( Table 14.4 ), while the secondary forms are associated with various underlying conditions and diseases, such as malignant hypertension, scleroderma, pregnancy, chemotherapy, anti-phospholipid antibodies, and transplant rejection, with less well-defined etiology and pathogenesis. Only the three major forms of primary thrombotic microangiopathies are sufficiently common to merit discusson. Shiga toxin–mediated HUS. As many as 75% of cases follow intestinal infection with Shiga toxin–producing E. coli, such as occurs following ingestion of contaminated ground meat (e.g., in hamburgers) and infections with Shigella dysenteriae type I. The pathogenesis is related to the effects of Shiga toxin. The basis for thrombus formation in small vessels, particularly in the kidney, is complex, but most studies suggest endothelial damage has a central role. Renal glomerular endothelial cells are vulnerable because they express the membrane receptor for Shiga toxin. At low doses, the toxin activates endothelial cells, leading to leukocyte adhesion, Table 14.4 Etiologic Classification of the Major Forms of Primary Thrombotic Microangiopathy ADAMTS13, vonWillebrandfactorcleavingprotease;HUS, hemolyticuremicsyndrome;TMA, thromboticmicroangiopathy;TTP, thromboticthrombocytopenicpurpura. http://ebooksmedicine.net increased endothelin production and decreased nitric oxide production (both favoring vasoconstriction), as well as other changes that may promote platelet adhesion and activation. At high doses, the toxin causes endothelial cell death. All of these alterations may contribute to the formation of thrombi, which tend to be most prominent in glomerular capillaries, afferent arterioles, and interlobular arteries. Atypical HUS is caused by acquired or hereditary abnormalities of factors that dampen activation of complement by the alternative pathway.The C5-9 membrane attack complex appears to have a central role, as a therapeutic antibody that inhibits this complex turns off platelet consumption and improves renal function.Interestingly, abnormalities of the alternative pathway of complement activation also may lead to C3 glomerulonephritis and dense deposit disease, as discussed earlier.
No studies have investigated phosphodiesterase-5 inhibitors in the treatment of HAPE, but reports have described their use in clinical practice.Inhaled nitric oxide and expiratory positive airway pressure may also be useful therapeutic measures but may not be available in high-altitude settings.Sustained-release nifedipine (30 mg), given once or twice daily, prevents HAPE in people who must ascend rapidly or who have a history of HAPE. Other drugs for the prevention of HAPE are listed in Table 476e-1 (footnote e). Although dexamethasone is listed for prevention, its adverse-effect profile requires close monitoring. Acetazolamide has been shown to blunt hypoxic pulmonary vasoconstriction in animal models, and this observation warrants further study in HAPE prevention. However, one large study failed to show a decrease in pulmonary vasoconstriction in partially acclimated individuals given acetazolamide. Early recognition is paramount in the treatment of HAPE, especially when it is not preceded by the AMS symptoms of headache and nausea. Fatigue and dyspnea at rest may be the only initial manifestations. Descent and the use of supplementary oxygen (aimed at bringing oxygen saturation to >90%) are the most effective therapeutic interventions. Exertion should be kept to a minimum, and the patient should be kept warm. Hyperbaric therapy in a portable altitude chamber may be used if descent is not possible and oxygen is not available. Oral sustained-release nifedipine (30 mg once or twice daily) can be used as adjunctive therapy. Inhaled β agonists, which are safe and convenient to carry, are useful in the prevention of HAPE and may be effective in its treatment, although no trials have yet been carried out. Inhaled nitric oxide and expiratory positive airway pressure may also be useful therapeutic measures but may not be available in high-altitude settings. No studies have investigated phosphodiesterase-5 inhibitors in the treatment of HAPE, but reports have described their use in clinical practice.In AMS, if symptoms abate (with or without acetazolamide), the patient may reascend gradually to a higher altitude.Unlike that in acute respiratory distress syndrome (another noncardiogenic pulmonary edema), the architecture of the lung in HAPE is usually well preserved, with rapid reversibility of abnormalities (Fig.476e-2).
One important aspect of this transition derives from the broad recognition observations.Speculative results do not belong in an official nosology, but at the same time, DSM must evolve in the context of other clinical research ini- tiatives in the field.Finding the right balance is critical.All of these efforts were directed toward the goal of enhancing the Clinical usefulness of DSM-5 as a guide in the diagnosis of mental disorders. Reliable diagnoses are essential for guiding treatment recommendations, identifying prevalence rates for mental health service planning, identifying patient groups for clinical and basic research, and documenting important public health information such as mor— bidity and mortality rates. As the understanding of mental disorders and their treatments has evolved, medical, scientific, and clinical professionals have focused on the character- istics of specific disorders and their implications for treatment and research. While DSM has been the cornerstone of substantial progress in reliability, it has been well recognized by both the American Psychiatric Association (APA) and the broad scientific com- munity working on mental disorders that past science was not mature enough to yield fully validated diagnoses—that is, to provide consistent, strong, and objective scientific validators of individual DSM disorders. The science of mental disorders continues to evolve. However, the last two decades since DSM-IV was released have seen real and durable progress in such areas as cognitive neuroscience, brain imaging, epidemiology, and genetics. The DSM-S Task Force overseeing the new edition recognized that research advances will require careful, iter— ative changes if DSM is to maintain its place as the touchstone classification of mental disor— ders. Finding the right balance is critical. Speculative results do not belong in an official nosology, but at the same time, DSM must evolve in the context of other clinical research ini- tiatives in the field. One important aspect of this transition derives from the broad recognition observations.These findings mean that DSM, like other medical disease classifications, should accomo- date ways to introduce dimensional approaches to mental disorders, including dimensions that cut across current categories.
25-75).The studies should be done with the patient in the right lateral decubitus position (Fig.When the patient is upright, the passage of water-soluble contrast material can be too rapid to demonstrate a small perforation.This may be due to obtaining the radiographic study with the patient in the upright position.Of concern is that there is a 10% false-negative rate.Mediastinal emphysema, a strong indica-tor of perforation, takes at least 1 hour to be demonstrated and is present in only 40% of patients. Mediastinal widening second-ary to edema may not occur for several hours. The site of perfo-ration also can influence the radiographic findings. In cervical perforation, cervical emphysema is common and mediastinal emphysema rare; the converse is true for thoracic perforations. Figure 25-73. Barium esophagogram showing a classical, smooth, contoured, punched-out defect of a leiomyoma.Brunicardi_Ch25_p1009-p1098.indd 108301/03/19 6:05 PM 1084SPECIFIC CONSIDERATIONSPART IIFrequently, air will be visible in the erector spinae muscles on a neck radiogram before it can be palpated or seen on a chest radiogram (Fig. 25-74). The integrity of the mediastinal pleura influences the radiographic abnormality in that rupture of the pleura results in a pneumothorax, a finding that is seen in 77% of patients. In two-thirds of patients, the perforation is on the left side; in one-fifth, it is on the right side; and in one-tenth, it is bilateral. If pleural integrity is maintained, mediastinal emphy-sema (rather than a pneumothorax) appears rapidly. A pleural effusion secondary to inflammation of the mediastinum occurs late. In 9% of patients, the chest radiogram is normal.The diagnosis is confirmed with a contrast esophagram, which will demonstrate extravasation in 90% of patients. The use of a water-soluble medium such as Gastrografin is preferred. Of concern is that there is a 10% false-negative rate. This may be due to obtaining the radiographic study with the patient in the upright position. When the patient is upright, the passage of water-soluble contrast material can be too rapid to demonstrate a small perforation. The studies should be done with the patient in the right lateral decubitus position (Fig. 25-75).The most favorable outcome is obtained following primary closure of the perforation within 24 hours, resulting in 80% to 90% survival.Figure 25-76 is an operative photograph taken through a left thoracotomy of an esophageal rupture following a pneumatic dilation for achalasia.The most common location for the injury is the left lateral wall of the esophagus, just above the GEJ.Figure 25-74.
The level of PrPSc in such cells is hypothesized to be sufficiently low as to be not detected by routine bioassay.(3) PrPSc may be present at low levels in some normal cells, where it performs some important, as yet unknown, function.Most individuals would be spared, while presentations in the elderly with an incidence of ~1 per million would be seen.In turn, prion diversity appears to be enciphered in the conformation of PrPSc, and thus prion strains seem to represent different conformers of PrPSc. In general, transmission of PrP prion disease from one species to another is inefficient, in that not all intracerebrally inoculated animals develop disease, and those that fall ill do so only after long incubation times that can approach the natural life span of the animal. This “species barrier” to transmission is correlated with the degree of similarity between the amino acid sequences of PrPC in the inoculated host and of PrPSc in the prion inoculum. The importance of sequence similarity between the host and donor PrP argues that PrPC directly interacts with PrPSc in the prion conversion process. Several different scenarios might explain the initiation of sporadic prion disease: (1) A somatic mutation may be the cause and thus follow a path similar to that for germline mutations in inherited disease. In this situation, the mutant PrPSc must be capable of targeting wild-type PrPC, a process known to be possible for some mutations but less likely for others. (2) The activation energy barrier separating wild-type PrPC from PrPSc could be crossed on rare occasions when viewed in the context of a population. Most individuals would be spared, while presentations in the elderly with an incidence of ~1 per million would be seen. (3) PrPSc may be present at low levels in some normal cells, where it performs some important, as yet unknown, function. The level of PrPSc in such cells is hypothesized to be sufficiently low as to be not detected by routine bioassay.The third possible mechanism is attractive because 453e-3 it suggests PrPSc is not simply a misfolded protein, as proposed for the first and second mechanisms, but that it is an alternatively folded molecule with a function.
The internal manipulation of these symbols constitutes thinking and their retention is the substance of memory.Viewed broadly, language is the means of symbolic representation of objects, actions, and events and, therefore, the mirror of all higher mental activity.Four fundamental types of cerebral cortex and their distribution in the cerebrum. The primary visual cortex has a preponderance of small neurons; hence, it was historically called “granular.” The primary motor cortex, by contrast, has relatively fewer small neurons and was described as “agranular.” (Reproduced with permission from Kandel ER, Schwartz JH, Jessel TM: Principles of Neural Science, 4th ed. New York, McGraw-Hill, 2000.) Figure 21-6. Connections involved in naming a seen object and in reading. The visual pattern is transferred from the visual cortex and association areas to the angular gyrus, which arouses the auditory pattern in the Wernicke area. The auditory pattern is transmitted to the Broca area through the arcuate fasciculus, where the articulatory form is aroused and transferred to the contiguous face area of the motor cortex. With destruction of the left visual cortex and splenium (or intervening white matter), the words perceived in the right visual cortex cannot cross over to the language areas and the patient cannot read. Chapter 21 Neurologic Disorders Caused by Lesions in Specific Parts of the Cerebrum Disorders of Speech and Language Speech and language functions are of fundamental human significance, both in social interaction and in private intellectual life. When they are disturbed as a consequence of brain disease, the functional loss exceeds in many ways all others in gravity—even blindness, deafness, and paralysis. The neurologist is concerned with all derangements of speech and language, including those of reading and writing because they are almost invariably manifestations of disease of the brain. Viewed broadly, language is the means of symbolic representation of objects, actions, and events and, therefore, the mirror of all higher mental activity. The internal manipulation of these symbols constitutes thinking and their retention is the substance of memory.Consequently, any disease process that interferes with speech or the understanding of spoken words touches the very core of the physician–patient relationship.Finally, the study of language disorders and the development of language (see Chap.27) serve to illuminate the relationship between psychologic functions and the anatomy and physiology of the brain.
The cerebral aqueduct (of Sylvius) traverses the midbrain and connects the third ventricle with the fourth ventricle.The third ventricle lies in the midline between the diencephalon on the two sides.They each connect with the third ventricle through one of the inter-ventricular foramina (of Monro).The lateral ventricles are situated within the two cerebral hemispheres.4.9 ).3rded.Philadelphia:ChurchillLivingstone;2006.) The thalamus sits at the upper end of the brainstem and is enclosed by the cerebrum with which it is highly interconnected (see Fig. 4.6B ). With a few exceptions, ascending information first reaches the thalamus, which conveys it to the cerebral cortex. These structures play a major role in many functions, including conscious awareness, volition, memory, and language. In addition to the cortex, the cerebrum contains a group of deep nuclei, the basal ganglia, that are interconnected with the cortex and thalamus and whose function will be described in The major functions of the different parts of the CNS are listed in Table 4.1 CSF fills the ventricular system, a series of interconnected spaces within the brain, and the subarachnoid space directly surrounding the brain. The intraventricular CSF reflects the composition of the brain’s extracellular space via free exchange across the ependyma, and the brain “floats” in the subarachnoid CSF to minimize the effect of external mechanical forces. The volume of CSF within the cerebral ventricles is approximately 30 mL, and that in the sub-arachnoid space is about 125 mL. Because about 0.35 mL of CSF is produced each minute, CSF is turned over more than three times daily. CSF is a filtrate of capillary blood formed largely by the choroid plexuses, which comprise pia mater, invaginating capillaries, and ependymal cells specialized for transport. The choroid plexuses are located in the lateral, third, and fourth ventricles (see Fig. 4.9 ). The lateral ventricles are situated within the two cerebral hemispheres. They each connect with the third ventricle through one of the inter-ventricular foramina (of Monro). The third ventricle lies in the midline between the diencephalon on the two sides. The cerebral aqueduct (of Sylvius) traverses the midbrain and connects the third ventricle with the fourth ventricle.The central canal of the spinal cord continues caudally from the fourth ventricle, although in adult humans the canal is not fully patent and continues to close with age.CSF escapes from the ventricular system through three apertures or foramina (a medial foramen of Magendie and two lateral foramina of Luschka) located in the roof of the fourth ventricle.
With poor insight: The individual thinks obsessive-compulsive disorder beliefs are probably true.Specify it: With good or fair insight: The individual recognizes that obsessive-compulsive dis- order beliefs are definitely or probably not true or that they may or may not be true.Note: Young children may not be able to articulate the aims of these behaviors or mental acts. B. The obsessions or compulsions are time-consuming (e.g., take more than 1 hour per day) or cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. The obsessive-compulsive symptoms are not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition. D. The disturbance is not better explained by the symptoms of another mental disorder (e.g.. excessive worries. as in generalized anxiety disorder; preoccupation with ap- pearance, as in body dysmorphic disorder; difficulty discarding or parting with posses- sions, as in hoarding disorder; hair pulling, as in trichotillomania [hair-pulling disorder]; skin picking, as in excoriation [skin-picking] disorder; stereotypies, as in stereotypic movement disorder; ritualized eating behavior, as in eating disorders; preoccupation with substances or gambling, as in substance-related and addictive disorders; preoc- cupation with having an illness, as in illness anxiety disorder; sexual urges or fantasies, as in paraphilic disorders; impulses, as in disruptive, impulse-control, and conduct dis- orders; guilty ruminations, as in major depressive disorder; thought insertion or delu- sional preoccupations, as in schizophrenia spectrum and other psychotic disorders; or repetitive patterns of behavior, as in autism spectrum disorder). Specify it: With good or fair insight: The individual recognizes that obsessive-compulsive dis- order beliefs are definitely or probably not true or that they may or may not be true. With poor insight: The individual thinks obsessive-compulsive disorder beliefs are probably true.Specify it: Tic-related: The individual has a current or past history of a tie disorder.Many individuals with obsessive-compulsive disorder (OCD) have dysfunctional beliefs.
There should also be a search for anemia, renal failure, chronic inflammatory disease such as temporal arteritis and polymyalgia rheumatica (sedimentation rate); an endocrine survey (thyroid, calcium, and cortisol and testosterone levels) and, in appropriate cases, an evaluation for an occult tumor are also in order in obscure cases. It must be remembered that chronic intoxication with alcohol, barbiturates, or other sedative drugs, some of which are given to suppress nervousness or insomnia, may contribute to fatigability. The rapid and recent onset of fatigue should always suggest the presence of an infection, a disturbance in fluid balance, gastrointestinal bleeding, or rapidly developing circulatory failure of either peripheral or cardiac origin. The features that suggest sleep apnea have been mentioned above and are discussed further in Chap. 18. Finally, it bears repeating fatigue must be distinguished from genuine muscular weakness. The demonstration of reduced power, reflex changes, fasciculations, and atrophy sets the case analysis along different lines, bringing up for particular consideration diseases of the peripheral nervous system or of the musculature. Rare, difficult-to-diagnose diseases that cause inexplicable muscle weakness and exercise intolerance are otherwise inevident hyperthyroidism, hyperparathyroidism, ossifying hemangiomas with hypophosphatemia, some of the periodic paralyses, hyperinsulinism, disorders of carbohydrate and lipid metabolism, and the mitochondrial myopathies, all of which are discussed in later chapters of the book on disease of muscle.They are probably best treated with gradually increasing exercise levels and perhaps with antidepressant medication, although this regimen has not always been successful.There are reports of success in treating these patients with mineralocorticoids (predicated on the above-mentioned orthostatic intolerance), estradiol patches, hypnosis, and a variety of other medical and nonmedical treatments.
Despite the heightened awareness and increased public focus on the crucial issues raised by these publications, there is limited evidence of significant progress toward making this country’s health care both safer and better (3).Adverse outcomes and near misses allow the organization to examine its processes of care with an eye to continuous improvement. In an assessment of the factors leading up to serious adverse events in hospitals, communication problems were the most frequently identified root cause, occurring in almost three-fourths of cases. No one should be hesitant to raise questions and concerns when an unsafe situation is observed. Drills and rehearsals for emergency situations improve outcomes and enhance safety. Hand washing using appropriate technique before and after every patient encounter should be considered mandatory. In the operating room, a preoperative verification process, a marking of the surgical site, and the performance of a time-out should be routine. Medication safety is a high priority for quality improvement initiatives. Avoiding abbreviations that may lead to medication error increases patient safety. Disruptive behavior in the hospital setting can have adverse effects on patient safety and overall quality of care. Professional organizations endorse active disclosure to the patient when adverse events occur, including those caused by error. Effective communication with office personnel and with patients is an essential element for creating a culture of safety in the office setting. What Is Quality Care? It has been more than a decade since the Institute of Medicine (IOM) published two seminal works in the fields of patient safety and medical care quality: To Err Is Human and Crossing the Quality Chasm (1,2). Despite the heightened awareness and increased public focus on the crucial issues raised by these publications, there is limited evidence of significant progress toward making this country’s health care both safer and better (3).Leaders in the patient safety movement have called for the redesign of education for health care professionals in order to equip these individuals with the essential knowledge, skill, and attitude required to function safely and effectively in the health care delivery environment of the 21st century.
The Biology of Bacterial Meningitis The immediate effect of bacteria or other microorganisms in the subarachnoid space is to cause an inflammatory reaction in the pia and arachnoid as well as in the cerebrospinal fluid (CSF).In the adult the most common spontaneous or community-acquired pathogenic organisms are pneumococcus (Streptococcus pneumoniae), meningococcus (Neisseria meningitidis), group B streptococcus, Listeria monocytogenes, and staphylococcus; in the neonate, Escherichia coli and group B streptococcus; in the infant and unvaccinated child, H. influenzae. By contrast, when septic material embolizes from infected lungs, pulmonary arteriovenous fistulas, or congenital heart lesions, or extends directly from ears or sinuses, more than one type of bacterial flora common to these sites may be transmitted. Such “mixed infections” pose difficult problems in therapy. Occasionally in these latter conditions, culture of the causative organisms may be unsuccessful, even from the pus of an abscess (mainly because of difficulty in culturing for anaerobic organisms and due to the prior use of antibiotics). Infections that follow neurosurgery or the insertion of a cranial appliance are usually staphylococcal or due to anaerobic gram negative organisms; a small number are a result of mixed flora, including anaerobic ones, or one of the enteric organisms. In determining the most likely invading organism, the age of the patient, the clinical setting of the infection (community-acquired, postsurgical, or nosocomial), the immune status of the patient, and evidence of systemic and local cranial disease all must be taken into account. The Biology of Bacterial Meningitis The immediate effect of bacteria or other microorganisms in the subarachnoid space is to cause an inflammatory reaction in the pia and arachnoid as well as in the cerebrospinal fluid (CSF).Infection also reaches the ventricles, either directly from the choroid plexuses or by reflux through the foramina of Magendie and Luschka.The first reaction to bacteria or their toxins is hyperemia of the meningeal venules and capillaries and an increased permeability of these vessels, followed shortly by exudation of protein and the migration of neutrophils into the pia and subarachnoid space.
LTB4 also causes inositol trisphosphate release via the BLT1 receptor, causing activation, degranulation, and superoxide anion generation in leukocytes.This receptor couples through a Gi-type G protein and leads to inhibition of cAMP synthesis and increases in intracellular Ca2+ in a variety of cell types.Two receptors exist for LTB4 (BLT1 and BLT2) and for LTC4/LTD4 (cysLT1 and cysLT2). It appears that LTE4 functions through one or more receptors distinct from cysLT1/cysLT2, with some evidence that the orphan receptor GPR99 and the ADP receptor P2Y12 may function as LTE4 receptors. The formyl peptide (fMLP)-1 receptor can be activated by lipoxin A4 and consequently has been termed the ALX receptor. Receptor heterodimerization has been reported for a number of the eicosanoid receptors, providing for additional receptor subtypes from the currently identified gene products. All of these receptors are G protein-coupled; properties of the best-studied receptors are listed in Table 18–1. EP2, EP4, IP, and DP1 receptors activate adenylyl cyclase via Gs. This leads to increased intracellular cAMP levels, which in turn activate specific protein kinases (see Chapter 2). EP1, FP, and TP activate phosphatidylinositol metabolism, leading to the formation of inositol trisphosphate, with subsequent mobilization of Ca2+ stores and an increase of free intracellular Ca2+. TP also couples to multiple G proteins, including G12/13 and G16, to stimulate small G protein signaling pathways, and may activate or inhibit adenylyl cyclase via Gs (TPα) or Gi (TPβ), respectively. EP3 isoforms can couple to both increased intracellular calcium and to increased or decreased cAMP. The DP2 receptor (also known as the chemoattractant receptor-homologous molecule expressed on Th2 cells, or CRTh2), which is unrelated to the other prostanoid receptors, is a member of the fMLP receptor superfamily. This receptor couples through a Gi-type G protein and leads to inhibition of cAMP synthesis and increases in intracellular Ca2+ in a variety of cell types. LTB4 also causes inositol trisphosphate release via the BLT1 receptor, causing activation, degranulation, and superoxide anion generation in leukocytes.CysLT1 and cysLT2 couple to Gq, leading to increased intracellular Ca2+.Studies have also placed Gi downstream of cysLT2.An orphan receptor, GPR17, binds cysLTs and may negatively regulate the function of cysLT1, but its physiologic role remains ill defined.
Muscle weakness and atrophy, hypotonia, and contractures occur less regularly and are overshadowed by the liver disease.Hepatomegaly as a result of accumulation of an abnormal polysaccharide is a universal finding.This is a progressive disease of infancy and early childhood, characterized by cirrhosis and chronic hepatic failure, usually with death in the second or third year.Other Forms of Glycogenosis (See Table 45-5) Of the remaining glycogen storage diseases, type III (debranching enzyme deficiency; Cori-Forbes disease, AGL Mutation) affects muscle but only inconsistently. The childhood form is characterized mainly by a benign hepatopathy, sometimes accompanied by diminished muscle strength and tone. An adult form beginning in the third and fourth decades presents with proximal and distal myopathy. The course is slowly progressive and may be associated with wasting of the leg and hand muscles. Several patients have developed weakness during adult life complained of rapid fatigue and aching of muscles, occurring with exertion and first noticed at an early age. Serum CK values were elevated and the EMG showed a myopathic picture as well as increased insertional activity, pseudomyotonic discharges, and fibrillation potentials. Rarely in the adult form, glycogen also accumulates in the peripheral nerves, giving rise to mild symptoms of polyneuropathy. The enzymatic defect is one of amylo-1,6-glucosidase deficiency. Disturbance of skeletal muscle is even less prominent in type IV glycogenosis (branching enzyme deficiency, or Andersen disease, which is also implicated in the polyglucosan disease that causes a special neuropathy discussed in Chap. 43, a motor system disease with flaccid bladder, or a leukoencephalopathy with dementia). This is a progressive disease of infancy and early childhood, characterized by cirrhosis and chronic hepatic failure, usually with death in the second or third year. Hepatomegaly as a result of accumulation of an abnormal polysaccharide is a universal finding. Muscle weakness and atrophy, hypotonia, and contractures occur less regularly and are overshadowed by the liver disease.The remaining nonlysosomal glycogenoses (types VIII through XI) need only be mentioned briefly.They are all rare and clinically heterogeneous, and a myopathy— characterized by intolerance to exercise, cramps, myoglobinuria, elevated CK, and, sometimes, renal failure—has been observed in a small proportion of them.
IBD includes Crohn’s disease (CD), which can involve any part of the gut, and ulcerative colitis (UC), which affects only the colon.Available @ StudentConsult.com The peak incidence of IBD in children is in the second decadeof life.The treatment is surgical excision.When the level of suspicion is high, surgical or laparoscopic investigation is warranted.When no ganglion cells areshown in the submucosal plexus, accompanied by nerve trunk hyperplasia, the diagnosis is certain. Barium enema and anorectal manometry may be used before biopsy, butfalse-negative and false-positive results can occur. Therapy is surgical. When the bowel is markedly distended orinflamed, an initial colostomy usually is performed abovethe aganglionic segment, followed weeks later by one of several definitive repair procedures. The transanal pull-throughexcises the aganglionic bowel and creates a primary colorectal anastomosis without laparotomy. This procedure can beconsidered in patients with uncomplicated involvement limited to the rectosigmoid region. Meckel diverticulum is a remnant of the fetal omphalomesenteric duct and is an outpouching of the distal ileumpresent in 1% to 2% of the population. Although most diverticula are asymptomatic throughout life, some cause massive, painless GI bleeding. Ectopic gastric tissue within thediverticulum causes ulceration of mucosa in the adjacentileum. Meckel diverticulum may be a lead point for intussusception or may enable twisting (volvulus) of neighboring bowel around its vascular supply. Diverticulitis mimicsappendicitis. Diagnosis may be made in most cases by technetium scan (Meckel scan), which labels the acid-producingmucosa. Because not all diverticula are seen, ultrasound, barium enteroclysis, or video capsule endoscopy may beuseful. When the level of suspicion is high, surgical or laparoscopic investigation is warranted. The treatment is surgical excision. Available @ StudentConsult.com The peak incidence of IBD in children is in the second decadeof life. IBD includes Crohn’s disease (CD), which can involve any part of the gut, and ulcerative colitis (UC), which affects only the colon.IBD is uncommon in tropical and Third World countries.It is more common in Jewish than in other ethnic populations.Geneticfactors play a role in susceptibility, with significantly higher riskif there is a family history of IBD.Having a first-degree relative with IBD increases the risk about 30-fold.
T cell–mediated cytotoxicity may contribute directly taBLe 122-3 antiBoDies to CeLL surfaCe or synaptiC antigens, synDromes, anD assoCiateD tumors to cell death in these PNDs.The infiltrating T cells are often in close contact with neurons undergoing degeneration, suggesting a primary pathogenic role.They are caused by mechanisms other than metastasis or by any of the complications of cancer such as coagulopathy, stroke, metabolic and Anti-CRMP5 (CV2) Encephalomyelitis, chorea, SCLC, thymoma, other optic neuritis, uveitis, nutritional conditions, infections, and side effects of cancer therapy. In 60% of patients, the neurologic symptoms precede the cancer diagnosis. Anti-Ma proteins Limbic, hypothalamic, Testicular (Ma2), Clinically disabling PNDs occur in 0.5–1% of all cancer patients, but they affect 2–3% of patients with neuroblastoma or small-cell lung can Anti-amphiphysin Stiff-person syndrome, Breast, SCLC cer (SCLC) and 30–50% of patients with thymoma or sclerotic myeloma. Recoverin, bipolar Cancer-associated retinopathy SCLC (CAR), melanoma cell antibodies, (CAR) (MAR) Most PNDs are mediated by immune responses triggered by neuronal othersa proteins (onconeuronal antigens) expressed by tumors. In PNDs of the central nervous system (CNS), many antibody-associated immune Anti-GAD Stiff-person, cerebellar Infrequent tumor responses have been identified (Table 122-2). These antibodies react syndromes, limbic encephalitis association (thymoma) with the patient’s tumor, and their detection in serum or cerebrospinal aA variety of target antigens have been identified. fluid (CSF) usually predicts the presence of cancer. When the anti- Abbreviations: CRMP, collapsing response-mediator protein; SCLC, small-cell lung cancer. gens are intracellular, most syndromes are associated with extensive infiltrates of CD4+ and CD8+ T cells, microglial activation, gliosis, and variable neuronal loss. The infiltrating T cells are often in close contact with neurons undergoing degeneration, suggesting a primary pathogenic role. T cell–mediated cytotoxicity may contribute directly taBLe 122-3 antiBoDies to CeLL surfaCe or synaptiC antigens, synDromes, anD assoCiateD tumors to cell death in these PNDs.This complex immunopathogenesis may underlie the resistance of many of Anti-AChR Myasthenia gravis Thymoma (muscle)a these conditions to therapy.
Only the maternally derived allele of the gene normally is active.UBE3A encodes for a ubiquitin ligase, a family of enzymes that targets other cellular proteins for proteasomal degradation (Chapter 1) through the addition of ubiquitin moieties.Conversely, a distinct gene, UBE3A, that also maps to the same region of chromosome 15 isimprinted on thepaternalchromosome.In contrast to Prader-Willi syndrome, patients with the phenotypically distinct Angelman syndrome are born with a deletion of the same chromosomal region derived from their mothers. Patients with Angelman syndrome also are mentally retarded, but in addition they present with ataxic gait, seizures, and inappropriate laughter. Because of the laughter and ataxia, this syndrome has been called the happy puppet syndrome. A comparison of these two syndromes clearly demonstrates the “parent-oforigin” effects on gene function. If all the paternal and maternal genes contained within chromosome 15 were expressed in an identical fashion, clinical features resulting from these deletions would be expected to be identical regardless of the parental origin of chromosome 15. The molecular basis of these two syndromes can be understood in the context of imprinting ( Fig. 7.20 ). A set of genes on the maternal chromosome at 15q12 is imprinted (and hence silenced), so the paternal chromosome provides the only functional alleles. When these are lost as a result of a deletion (in the paternal chromosome), the patient develops Prader-Willi syndrome. Among the set of genes that are deleted in Prader-Willi syndrome, the most likely culprit is believed to be a gene cluster encoding multiple distinct small nucleolar RNAs (snoRNAs), which are involved in messenger RNA processing. Conversely, a distinct gene, UBE3A, that also maps to the same region of chromosome 15 isimprinted on thepaternalchromosome. UBE3A encodes for a ubiquitin ligase, a family of enzymes that targets other cellular proteins for proteasomal degradation (Chapter 1) through the addition of ubiquitin moieties. Only the maternally derived allele of the gene normally is active.The neurologic manifestations of Angelman are principally because of a lack of UBE3A expression in specific regions of the brain.Molecular studies of cytogenetically normal patients with Prader-Willi syndrome have shown that in some cases, both of the structurally normal copies of chromosome 15 are derived from the mother.
Patients with unilateral injury usually are neurologically intact.Hyperflexion/rotation can cause a unilateral jumped facet, whereas hyperflexion/distraction leads to bilateral jumped facets.In a hyperflexion injury, the supe-rior facet can “jump” over the inferior facet of the level above if the joint capsule is torn.Several strong ligaments connect the dens to C1 and to the base of the skull. Odontoid fractures usually result from flexion forces. Odontoid fractures are classified as type I, II, or III. A type I fracture involves the tip only. A type II fracture passes through the base of the odontoid process. A type III fracture passes through the body of C2. Types II and III are considered unstable and should be externally immobilized or fused surgically. Surgery often is undertaken for widely displaced fractures (poor chance of fus-ing) and for those that fail external immobilization. Type I frac-tures usually fuse with external immobilization only.Hangman’s Fracture Traditionally considered a hyperexten-sion/distraction injury from placement of the noose under the angle of the jaw, hangman’s fractures also may occur with hyperextension/compression, as with diving accidents, or hyper-flexion. The injury is defined by bilateral C2 pars interarticularis fractures. The pars interarticularis is the bone between superior and inferior facet joints. Thus, the posterior bony connection between C1 and C3 is lost. Hangman’s fractures heal well with external immobilization. Surgery is indicated if there is spinal cord compression or after failure of external immobilization.Jumped Facets—Hyperflexion Injury The facet joints of the cervical spine slope forward. In a hyperflexion injury, the supe-rior facet can “jump” over the inferior facet of the level above if the joint capsule is torn. Hyperflexion/rotation can cause a unilateral jumped facet, whereas hyperflexion/distraction leads to bilateral jumped facets. Patients with unilateral injury usually are neurologically intact.42-11).Thoracolumbar The thoracic spine is stabilized significantly by the rib cage.The lumbar spine has comparatively large vertebrae.Thus, the thoracolumbar spine has a higher thresh-old for injury than the cervical spine.
Infants who have IUGR and SGA secondary to congenital infection, chromosomal abnormalities, or constitutional syndromes remain small throughout life.Postnatal growth and development depend in part on the etiology, the postnatal nutritional intake, and the social environment.Hepatosplenomegaly, jaundice, and skin rashes in addition to ocular disorders, Age (young and advanced) Cigarette smoking Genetics (short stature, weight) Illnesses during pregnancy (preeclampsia, severe diabetes, chronic hypertension, connective tissue disease) Infections (intrauterine) Lack of good prenatal care Oligohydramnios Poor nutrition Race (African American) Chromosomal abnormality and nonchromosomal syndromes Congenital infections Inborn errors of metabolism Multiple gestations Insulin resistance or reduced insulin or insulin-like growth factor-1 Antimetabolites (methotrexate) Heavy metals (mercury, lead) Hydantoin Narcotics (morphine, methadone) Steroids (prednisone) Substance and illicit drug use (alcohol, cocaine) Warfarin such as chorioretinitis, cataracts, glaucoma, and cloudy cornea, suggest the presence of a congenital infection or inborn error of metabolism. Infants with severe IUGR or SGA, particularly in conjunction with fetal distress, may have problems at birth that include respiratory acidosis, metabolic acidosis, asphyxia, hypoxemia, hypotension, hypoglycemia, polycythemia, meconium aspiration syndrome, and persistent pulmonary hypertension of the newborn. Management of IUGR and SGA infants is usually symptomatic and supportive. The diagnostic evaluation at birth should be directed at identifying the cause of the IUGR and SGA, if possible. The consequences of IUGR and SGA depend on the etiology, severity, and duration of growth retardation. The mortality rates of infants who are severely affected are 5 to 20 times those of infants who are appropriate for gestational age. Postnatal growth and development depend in part on the etiology, the postnatal nutritional intake, and the social environment. Infants who have IUGR and SGA secondary to congenital infection, chromosomal abnormalities, or constitutional syndromes remain small throughout life.Available @ StudentConsult.com Hydrops fetalis is caused by immune and nonimmune conditions.Hydrops fetalis is a fetal clinical condition of excessivefluid accumulation in the skin and one or more other bodycompartments, including the pleural space, peritoneal cavity,pericardial sac, or placenta with resultant high morbidity andmortality.
Persistent sepsis or collections on CT scan may require further radical surgical debridement.Chronic Mediastinitis.Blood cell counts and serial CT scans may also be required.New York, NY: Elsevier/Churchill Livingstone; 2002.Debridement may need to be repeated and other planes and cavities explored depending on the patient’s clinical status.Acute mediastinitis is a true surgical emergency; treatment must be instituted immediately and aimed at correcting the primary problem, such as the esophageal perforation or oro-pharyngeal abscess, and debridement and drainage of the spreading infectious process within the mediastinum, neck, pleura, and other tissue planes. Antibiotics, fluid resusci-tation, and other supportive measures are also important. Brunicardi_Ch19_p0661-p0750.indd 73501/03/19 7:01 PM 736SPECIFIC CONSIDERATIONSPART IITable 19-32Etiologic factors in acute mediastinitisEsophageal perforation Iatrogenic Balloon dilatation (for achalasia) Bougienage (for peptic stricture) Esophagoscopy Sclerotherapy (for variceal bleeding) Spontaneous Postemetic (Boerhaave’s syndrome) Straining during: Elimination Weight lifting Seizure Pregnancy Childbirth Ingestion of foreign bodies Trauma Blunt Penetrating Postsurgical Infection Anastomotic leak Erosion by cancerDeep sternotomy wound infectionOropharynx and neck infectionsLudwig’s anginaQuinsyRetropharyngeal abscessCellulitis and suppurative lymphadenitis of the neckInfections of the lung and pleuraSubphrenic abscessRib or vertebral osteomyelitisHematogenous or metastatic abscessReproduced with permission from Pearson FG, Cooper JD, Deslauriers J, et al: Thoracic Surgery, 2nd ed. New York, NY: Elsevier/Churchill Livingstone; 2002.Debridement may need to be repeated and other planes and cavities explored depending on the patient’s clinical status. Blood cell counts and serial CT scans may also be required. Persistent sepsis or collections on CT scan may require further radical surgical debridement.Chronic Mediastinitis.Chronic, low-grade inflammation leads to fibrosis and scarring, which can, in some patients, result in entrapment and compression of the low-pressure veins (including the SVC and innominate and azy-gos veins), the esophagus, and pulmonary arteries.There is no definitive treatment.
Typically, a suspension of cells is treated with certain inactivated viruses or with polyethylene glycol, each of which alters the plasma membranes of cells in a way that induces them to fuse.It is possible to fuse one cell with another to form a heterokaryon, a combined cell with two separate nuclei.B lymphocytes normally have a limited life-span in culture, but individual antibody-producing B lymphocytes from an immunized mouse, when fused with cells derived from a transformed B lymphocyte cell line, can give rise to hybrids that have both the ability to make a particular antibody and the ability to multiply indefinitely in culture. These hybridomas are propagated as individual clones, each of which provides a permanent and stable source of a single type of monoclonal antibody. Each type of monoclonal antibody recognizes a single type of antigenic site—for example, a particular cluster of five or six amino acid side chains on the surface of a protein. Their uniform specificity makes monoclonal antibodies much more useful than conventional antisera for many purposes. An important advantage of the hybridoma technique is that monoclonal antibodies can be made against molecules that constitute only a minor component of a complex mixture. In an ordinary antiserum made against such a mixture, the proportion of antibody molecules that recognize the minor component would be too small to be useful. But if the B lymphocytes that produce the various components of this antiserum are made into hybridomas, it becomes possible to screen individual hybridoma clones from the large mixture to select one that produces the desired type of monoclonal antibody and to propagate the selected hybridoma SUSPENSION OF TWO CELL three clones of hybrid cellsTYPES CENTRIFUGED WITH A FUSING AGENT ADDED SELECTIVE MEDIUM FORMATION OF PROLIFERATE. THESE HETEROKARYONS, BECOME HYBRID WHICH ARE CELLS, WHICH ARE THEN CULTURED THEN CLONED Figure 8–4 The production of hybrid cells. It is possible to fuse one cell with another to form a heterokaryon, a combined cell with two separate nuclei. Typically, a suspension of cells is treated with certain inactivated viruses or with polyethylene glycol, each of which alters the plasma membranes of cells in a way that induces them to fuse.Such hybrid cells can give rise to immortal hybrid cell lines.If one of the parent cells was from a tumor cell line, the hybrid cell is called a hybridoma.indefinitely so as to produce that antibody in unlimited quantities.In principle, therefore, a monoclonal antibody can be made against any protein in a biological sample.
In the United States, the cause is usually viral or bacterial bronchitis.While precise epidemiologic data are lacking, the most common etiology of hemoptysis is infection of the medium-sized airways.For most patients, any degree of hemoptysis can cause anxiety and often prompts medical evaluation.The tendency of narcotic cough suppressants to cause drowsiness and constipation and their potential for addictive dependence limit their appeal for longterm use. Dextromethorphan is an over-the-counter, centrally acting cough suppressant with fewer side effects and less efficacy than the narcotic cough suppressants. Dextromethorphan is thought to have a different site of action than narcotic cough suppressants and can be used in combination with them if necessary. Benzonatate is thought to inhibit neural activity of sensory nerves in the cough-reflex pathway. It is generally free of side effects; however, its effectiveness in suppressing cough is variable and unpredictable. Case series have reported benefit from off-label use of gabapentin or amitriptyline for chronic idiopathic cough. Novel cough suppressants without the limitations of currently available agents are greatly needed. Approaches that are being explored include the development of neurokinin receptor antagonists, type 1 vanilloid receptor antagonists, and novel opioid and opioid-like receptor agonists. Hemoptysis, the expectoration of blood from the respiratory tract, can arise at any location from the alveoli to the glottis. It is important to distinguish hemoptysis from epistaxis (bleeding from the nasopharynx) and hematemesis (bleeding from the upper gastrointestinal tract). Hemoptysis can range from the expectoration of blood-tinged sputum to that of life-threatening large volumes of bright red blood. For most patients, any degree of hemoptysis can cause anxiety and often prompts medical evaluation. While precise epidemiologic data are lacking, the most common etiology of hemoptysis is infection of the medium-sized airways. In the United States, the cause is usually viral or bacterial bronchitis.Worldwide, the most common cause of hemoptysis is infection with Mycobacterium tuberculosis, presumably because of the high prevalence of tuberculosis and its predilection for cavity formation.While these are the most common causes, the differential diagnosis for hemoptysis is extensive, and a step-wise approach to evaluation is appropriate.
(Adapted from P.J.Colored lines within the circle are then used to indicate the shown in blue, reveal the amplified DNA sequences (see the highly amplified regions indicated).Many of these changes were found repeatedly, suggesting that they contain cancer-critical genes whose loss (tumor suppressor genes) or gain (oncogenes) confers a selective advantage. Whole-genome analysis also helps to explain some cancers that seem, at first sight, to be exceptions to the general rules. An example is retinoblastoma, with its early onset during childhood. If cancers in general require an accumulation of many genetic changes and are thus diseases of old age, what makes retinoblastoma different? Whole-genome sequencing confirms that in retinoblastoma, the tumor cells contain loss-of-function mutations in the Rb gene; but, astonishingly, they contain practically no mutations or genome rearrangements that affect any other oncogene or tumor suppressor gene. Instead, they contain many epigenetic modifications, which alter the level of expression of many known cancer-critical genes—as many as 15 in one well-analyzed case. Many Mutations in Tumor Cells are Merely Passengers Cancer cells generally contain many mutations in addition to gross chromosome abnormalities: point mutations can be scattered over the genome as a whole at a rate of about one per million nucleotide pairs, in addition to the abnormalities Figure 20–24 The chromosomal rearrangements in breast cancer cells. The results of an extensive DNA sequencing analysis performed on two different primary tumors are displayed as “Circos plots.” In each plot, the reference DNA sequences of the 22 autosomes and single sex chromosome (X) of a normal human female (3.2 billion nucleotide pairs) are aligned end-to-end to form a circle. Colored lines within the circle are then used to indicate the shown in blue, reveal the amplified DNA sequences (see the highly amplified regions indicated). (Adapted from P.J.attributed to chromosome breakage and rejoining.Systematic surveys of the pro-tein-coding genes in common solid tumors—such as those of the breast, colon, brain, or pancreas—have revealed that an average of 33 to 66 genes have undergone somatic mutation affecting the sequence of their protein product.
When managed by an experienced team, the most frequent complication, infection, can be minimized (24).Proper daily care is required to avoid infectious complications.Only intravenous access lines in the right atrium, superior vena cava, or inferior vena cava can be truly deemed central lines (23).Clinical trials demonstrate that TPN can improve nutritional status as measured by biochemical assays, immune function, and nitrogen balance. The effect of TPN on clinical outcome is less well established. Despite what seems reasonable, based on common sense and preoperative nutritional parameters, the data do not support TPN for mild to moderately malnourished patients. With severe malnutrition, preoperative TPN seems to be beneficial and should be instituted. Route of Administration After the decision is made that nutritional support is required, the appropriate route of administration must be determined. Enteral nutrition should be considered primarily because it is easy to deliver, associated with the fewest complications, linked to enhanced wound healing, and relatively inexpensive (21). Contraindications to this route of delivery include intestinal obstruction, gastrointestinal bleeding, and diarrhea. Many types of preparations are commercially available and can be chosen based on their caloric content, fat content, protein content, osmolality, viscosity, and price. Depending on the patient’s problem, the route of delivery may be through a Dobhoff feeding tube, a gastrostomy tube, or a feeding jejunostomy tube (22). If the gastrointestinal tract is unusable for more than 7 days postoperatively, TPN should be implemented. Total parenteral nutrition must be delivered through a central vein and has wide acceptance as a means of providing nutritional support for surgically ill patients. It must be delivered through a subclavian or internal jugular vein, and the catheter must be placed using meticulous sterile surgical technique. Only intravenous access lines in the right atrium, superior vena cava, or inferior vena cava can be truly deemed central lines (23). Proper daily care is required to avoid infectious complications. When managed by an experienced team, the most frequent complication, infection, can be minimized (24).When given by TPN infusion, the dextrose tolerance in critically ill patients is 5 mg/kg/min (24).Insulin should be used to maintain serum glucose concentration between 150 and 250 mg/dL, and it may be added directly to the TPN solution.4.Fats.Lipids in a 10% to 20% emulsion can be given as further caloric supplement and supply the essential fatty acids, linoleic acid, and α-linoleic acids.
372e-7).Once engagement of mature T cell TCR by foreign peptide occurs in the context of self-MHC class I or class II molecules, binding of non-antigen-specific adhesion ligand pairs such as CD54-CD11/CD18 and CD58-CD2 stabilizes MHC peptide-TCR binding, and the expression of these adhesion molecules is upregulated (Fig.Whereas it is generally agreed that the TCR-αβ receptor recognizes peptide antigens in the context of MHC class I or class II molecules, lipids in the cell wall of intracellular bacteria such as M. tuberculosis can also be presented to a wide variety of T cells, including subsets of TCR-γδ T cells, and a subset of CD8+ TCR-αβ T cells. Importantly, bacterial lipid antigens are not presented in the context of MHC class I orIImolecules,butratherarepresentedinthecontextofMHC-related CD1 molecules. Some γδ T cells that recognize lipid antigens via CD1 molecules have very restricted TCR usage, do not need antigen priming to respond to bacterial lipids, and may actually be a form of innate rather than acquired immunity to intracellular bacteria. Just as foreign antigens are degraded and their peptide fragments presented in the context of MHC class I or class II molecules on APCs, endogenous self-proteins also are degraded, and self-peptide fragments are presented to T cells in the context of MHC class I or class II molecules on APCs. In peripheral lymphoid organs, there are T cells that are capable of recognizing self-protein fragments but normally are anergic or tolerant, i.e., nonresponsive to self-antigenic stimulation, due to lack of self-antigen upregulating APC co-stimulatory molecules such as B7-1 (CD80) and B7-2 (CD86) (see below). Once engagement of mature T cell TCR by foreign peptide occurs in the context of self-MHC class I or class II molecules, binding of non-antigen-specific adhesion ligand pairs such as CD54-CD11/CD18 and CD58-CD2 stabilizes MHC peptide-TCR binding, and the expression of these adhesion molecules is upregulated (Fig. 372e-7).372e-7).Importantly, during T cell activation, the CD45 molecule, with protein tyrosine phosphatase activity, is partitioned away from the TCR complex to allow activating phosphorylation events to occur.
Claudins constitute a family of proteins (20 to 27 kilodaltons) that have recently been identified as integral components of zonula occludens strands.However, several types of epithelial cells do not have occludin within their strands, but they still possess well-developed and fully functional zonulae occludentes.Occludin is present in most occluding junctions.The actual sites of protein interaction between the cells form the anastomosing network. 100,000. (Reprinted with permission from Hull BE, Staehelin LA. Functional significance of the variations in the geometrical organization of tight junction networks. J Cell Biol 1976;68:688–704.) FIGURE 5.16 • Molecular structure of zonula occludens. Diagram showing three transmembrane proteins involved in the formation of zonula occludens: occludin, claudin, and junctional adhesion molecule (JAM). Occludin and claudin have four transmembrane domains with two extracellular loops, but JAM has only a single transmembrane domain, and its extracellular portion possesses two immunoglobulinlike loops. Several major associated proteins of the occluding junction and their interactions with each other are visible. Note that one of the associated proteins, ZO-1, interacts with the cell cytoskeleton binding actin filaments. Several proteins are involved in the formation of zonula occludens strands. Zonula occludens strands correspond to the location of the rows of transmembrane proteins. Three major groups of transmembrane proteins are found in the zonula occludens (Fig. 5.16; Table 5.3): Occludin, a 60-kilodalton protein, was the first protein identified in the zonula occludens. It participates in maintaining the barrier between adjacent cells as well as the barrier between the apical and lateral domains. Occludin is present in most occluding junctions. However, several types of epithelial cells do not have occludin within their strands, but they still possess well-developed and fully functional zonulae occludentes. Claudins constitute a family of proteins (20 to 27 kilodaltons) that have recently been identified as integral components of zonula occludens strands.In addition, claudins (especially claudin-2 and claudin-16) are able to form extracellular aqueous channels for the paracellular passage of ions and other small molecules.About 24 different members of the claudin family have been characterized to date.Mutations in the gene encoding claudin-14 have been recently linked to human hereditary deafness.
The normal pericardium, by exerting a restraining force, prevents sudden dilation of the cardiac chambers, especially the right atrium and ventricle, during exercise and with hypervolemia.β-Adrenergic blocking agents and L-type calcium channel blockers slow AV nodal conduction and improve symptoms; cardiac glycosides should be avoided, as they may increase contractility and worsen obstruction. Symptoms exacerbated by atrial fibrillation may persist despite adequate rate control due to loss of AV synchrony and may require restoration of sinus rhythm. Disopyramide and amiodarone are the preferred antiarrhythmic agents, with radiofrequency ablation considered for medically refractory cases. Anticoagulation to prevent embolic stroke in atrial fibrillation is recommended. PROGNOSIS The general prognosis for hypertrophic cardiomyopathy is good, better than in early studies of referral populations. For patients diagnosed as adults, survival is comparable to an age-matched population without cardiomyopathy. The sudden death risk is less than 1% per year; however, up to 1 in 20 patients will progress to overt systolic dysfunction with a reduced ejection fraction with or without dilated remodeling (“burned out” or end-stage hypertrophic cardiomyopathy). These patients suffer from low cardiac output and have a high risk of death from progressive heart failure and sudden death unless they undergo cardiac transplantation. aImplantable cardioverter-defibrillator advised for patients with prior arrest or sustained ventricular tachycardia regardless of other risk factors. b Prognostic value most applicable to patients less than 40 years old. Abbreviation: LV, left ventricle. Pericardial Disease Eugene Braunwald NORMAL FUNCTIONS OF THE PERICARDIUM The normal pericardium is a double-layered sac; the visceral peri-cardium is a serous membrane that is separated by a small quantity (15–50 mL) of fluid, an ultrafiltrate of plasma, from the fibrous parietal 288 pericardium. The normal pericardium, by exerting a restraining force, prevents sudden dilation of the cardiac chambers, especially the right atrium and ventricle, during exercise and with hypervolemia.Nevertheless, total absence of the pericardium, either congenital or after surgery, does not produce obvious clinical disease.In partial left pericardial defects, the main pulmonary artery and left atrium may bulge through the defect; very rarely, herniation and subsequent strangulation of the left atrium may cause sudden death.
[Note: In prokaryotes, FAS is a multienzyme complex.]It also is a component of CoA.4ʹ-Phosphopantetheine, a derivative of pantothenic acid (vitamin B5, see p. 385), carries acyl units on its terminal thiol (–SH) group and presents them to the catalytic domains of FAS during fatty acid synthesis.Acetyl CoA carboxylase long-term regulation: Prolonged consumption of a diet containing excess calories (particularly high-carbohydrate, low-fat diets) causes an increase in ACC synthesis, thereby increasing fatty acid synthesis. A low-calorie or a high-fat, low-carbohydrate diet has the opposite effect. [Note: ACC synthesis is upregulated by carbohydrate (specifically glucose) via the transcription factor carbohydrate response element–binding protein (ChREBP) and by insulin via the transcription factor sterol regulatory element–binding protein-1c (SREBP-1c). Fatty acid synthase (see C. below) is similarly regulated. The function and regulation of SREBP are described on p. 222.] Metformin, used in the treatment of type 2 diabetes, lowers plasma TAG through activation of AMPK, resulting in inhibition of ACC activity (by phosphorylation) and inhibition of ACC and fatty acid synthase expression (by decreasing SREBP-1c). Metformin lowers blood glucose by increasing AMPK-mediated glucose uptake by muscle. C. Eukaryotic fatty acid synthase The remaining series of reactions of fatty acid synthesis in eukaryotes is catalyzed by the multifunctional, homodimeric enzyme fatty acid synthase (FAS). The process involves the addition of two carbons from malonyl CoA to the carboxyl end of a series of acyl acceptors. Each FAS monomer is a multicatalytic polypeptide with six different enzymic domains plus a 4ʹphosphopantetheine-containing acyl carrier protein (ACP) domain. 4ʹ-Phosphopantetheine, a derivative of pantothenic acid (vitamin B5, see p. 385), carries acyl units on its terminal thiol (–SH) group and presents them to the catalytic domains of FAS during fatty acid synthesis. It also is a component of CoA. [Note: In prokaryotes, FAS is a multienzyme complex.]1.An acetyl group is transferred from acetyl CoA to the –SH group of the ACP.Domain: Malonyl/acetyl CoA–ACP transacylase.2.Next, this two-carbon fragment is transferred to a temporary holding site, the –SH group of a cysteine residue on the condensing enzyme domain (see [4] below).3.The now-vacant ACP accepts a three-carbon malonyl group from malonyl CoA.
Figure 6–71 Structure of a typical bacterial mRNA molecule.These subunits can then assemble on this or another mRNA molecule to begin a new round of protein synthesis.The ribosome then releases its bound mRNA molecule and separates into the large and small subunits.A set of translation initiation factors orchestrates this interaction, as well as the subsequent assembly of the large ribosomal subunit to complete the ribosome. Unlike a eukaryotic ribosome, a bacterial ribosome can readily assemble directly on a start codon that lies in the interior of an mRNA molecule, so long as a ribosome-binding site precedes it by several nucleotides. As a result, bac-AMINOACYL terial mRNAs are often polycistronic—that is, they encode several different pro teins, each of which is translated from the same mRNA molecule (Figure 6–71). In contrast, a eukaryotic mRNA generally encodes only a single protein, or more accurately, a single set of closely related proteins. Stop Codons Mark the End of Translation The end of the protein-coding message is signaled by the presence of one of three stop codons (UAA, UAG, or UGA) (see Figure 6–48). These are not recognized by a tRNA and do not specify an amino acid, but instead signal to the ribosome to stop translation. Proteins known as release factors bind to any ribosome with a stop codon positioned in the A site, forcing the peptidyl transferase in the ribosome to catalyze the addition of a water molecule instead of an amino acid to the peptidyl-tRNA (Figure 6–72). This reaction frees the carboxyl end of the growing polypeptide chain from its attachment to a tRNA molecule, and since only this etc. attachment normally holds the growing polypeptide to the ribosome, the com pleted protein chain is immediately released into the cytoplasm. The ribosome then releases its bound mRNA molecule and separates into the large and small subunits. These subunits can then assemble on this or another mRNA molecule to begin a new round of protein synthesis. Figure 6–71 Structure of a typical bacterial mRNA molecule.This property of their ribosomes permits bacteria to synthesize more than one type of protein from a single mRNA molecule.During translation, the nascent polypeptide moves through a large, water-filled tunnel (approximately 10 nm × 1.5 nm) in the large subunit of the ribosome.
3.Active uterine bleeding should not deter the prompt completion of cervical dilation.Retained blood in the endometrial cavity may be expelled during cervical dilation.Cervical dilation—As the cervix is being dilated, uterine bleeding often increases.2.Oxytocin infusion—This procedure is begun before the induction of anesthesia.It involves the following steps: 1.Partial Hydatidiform Mole Persistent tumor, usually nonmetastatic, develops in approximately 2% to 4% of patients with a partial mole, and chemotherapy is required to achieve remission (32). Patients who develop persistent disease have no distinguishing clinical or pathologic characteristics (33). Diagnosis Ultrasonography is a reliable and sensitive technique for the diagnosis of complete molar pregnancy. Because the chorionic villi exhibit diffuse hydropic swelling, complete moles produce a characteristic vesicular ultrasonographic pattern as soon as in the first trimester (Fig. 39.6). Ultrasonography may contribute to the diagnosis of partial molar pregnancy by demonstrating focal cystic spaces in the placental tissues and an increase in the transverse diameter of the gestational sac (34). When these criteria are present, the positive predictive value for partial mole is 90%. Figure 39.6 Ultrasonogram of a uterus showing a typical pattern of a complete hydatidiform mole. Note the characteristic vesicular ultrasonographic pattern. Treatment When molar pregnancy is diagnosed, the patient should be evaluated for the presence of associated medical complications, including preeclampsia, hyperthyroidism, electrolyte imbalance, and anemia. After the patient’s condition is stabilized, a decision must be made concerning the most appropriate method of evacuation. Suction Curettage Suction curettage is the preferred method of evacuation, regardless of uterine size, for patients who desire to preserve fertility (32). It involves the following steps: 1. Oxytocin infusion—This procedure is begun before the induction of anesthesia. 2. Cervical dilation—As the cervix is being dilated, uterine bleeding often increases. Retained blood in the endometrial cavity may be expelled during cervical dilation. Active uterine bleeding should not deter the prompt completion of cervical dilation. 3.The use of a 12-mm cannula is strongly advised to facilitate evacuation.If the uterus is larger than 14 weeks of gestation, one hand should be placed on top of the fundus, and the uterus should be massaged to stimulate uterine contraction and reduce the risk of perforation.4.
Neonates often present with an illness resembling bacterial sepsis, with fever, irritability, and lethargy.Serotype(s) of Indicated Virus generalized disease of tHe newborn Most serious enterovirus infections 1291 in infants develop during the first week of life, although severe disease can occur up to 3 months of age.The onset is usually insidious, and weakness occasionally extends to muscles that were not involved during the initial illness. The prognosis is generally good; progression to further weakness is usually slow, with plateau periods of 1–10 years. The postpolio syndrome is thought to be due to progressive dysfunction and loss of motor neurons that compensated for the neurons lost during the original infection and not to persistent or reactivated poliovirus infection. Other Enteroviruses An estimated 5–10 million cases of symptomatic disease due to enteroviruses other than poliovirus occur in the United States each year. Among neonates, enteroviruses are the most common cause of aseptic meningitis and nonspecific febrile illnesses. Certain clinical syndromes are more likely to be caused by certain serotypes (Table 228-1). nonspecific febrile illness (sUmmer grippe) The most common clinical manifestation of enterovirus infection is a nonspecific febrile illness. After an incubation period of 3–6 days, patients present with an acute onset of fever, malaise, and headache. Occasional cases are associated with upper respiratory symptoms, and some cases include nausea and vomiting. Symptoms often last for 3–4 days, and most cases resolve in a week. While infections with other respiratory viruses occur more often from late fall to early spring, febrile illness due to enteroviruses frequently occurs in the summer and early fall. Serotype(s) of Indicated Virus generalized disease of tHe newborn Most serious enterovirus infections 1291 in infants develop during the first week of life, although severe disease can occur up to 3 months of age. Neonates often present with an illness resembling bacterial sepsis, with fever, irritability, and lethargy.The illness can be complicated by myocarditis and hypotension, fulminant hepatitis and disseminated intravascular coagulation, meningitis or meningoencephalitis, or pneumonia.It may be difficult to distinguish neonatal enterovirus infection from bacterial sepsis, although a history of a recent virus-like illness in the mother provides a clue.
While studying the structure of a small gene that was sequenced during the Human Genome Project, an investigator notices that one strand of the DNA molecule contains 20 A, 25 G, 30 C, and 22 T. How many of each base is found in the complete double-stranded molecule?0.3.These patients are deficient in any one of several XP proteins required for nucleotide excision repair of pyrimidine dimers in ultraviolet radiation– damaged DNA. Double-strand breaks are repaired by nonhomologous end joining (error prone) or homologous recombination (“error free”). Methylation is not used for strand discrimination in eukaryotic mismatch repair. Uracil is removed from DNA molecules by a specific glycosylase in base excision repair, but a defect in this process does not cause XP. 0.2. Telomeres are complexes of DNA and protein that protect the ends of linear chromosomes. In most normal human somatic cells, telomeres shorten with each division. In stem cells and in cancer cells, however, telomeric length is maintained. In the synthesis of telomeres: A. telomerase, a ribonucleoprotein, provides both the RNA and the protein needed for synthesis. B. the RNA of telomerase serves as a primer. C. the RNA of telomerase is a ribozyme. D. the protein of telomerase is a DNA-directed DNA polymerase. E. the shorter 3′→5′ strand gets extended. F. the direction of synthesis is 3′→5′. Correct answer = A. Telomerase is a ribonucleoprotein particle required for telomere maintenance. Telomerase contains an RNA that serves as the template, not the primer, for the synthesis of telomeric DNA by the reverse transcriptase of telomerase. Telomeric RNA has no catalytic activity. As a reverse transcriptase, telomerase synthesizes DNA using its RNA template and so is an RNA-directed DNA polymerase. The direction of synthesis, as with all DNA synthesis, is 5′→3′, and it is the 3′-end of the already longer 5′→3′ strand that gets extended. 0.3. While studying the structure of a small gene that was sequenced during the Human Genome Project, an investigator notices that one strand of the DNA molecule contains 20 A, 25 G, 30 C, and 22 T. How many of each base is found in the complete double-stranded molecule?The two DNA strands are complementary to each other, with A base-paired with T and G base-paired with C. So, for example, the 20 A on the first strand would be paired with 20 T on the second strand, the 25 G on the first strand would be paired with 25 C on the second strand, and so forth.When these are all added together, the correct numbers of each base are indicated in choice B.
P, phosphorylation; PL, phospholamban; TnI, troponin I.The latter effect explains enhanced relaxation (lusitropic effect).An increased rate of relaxation results from the ability of cAMP to activate as well the protein phospholamban, situated on the membrane of the SR, that controls the rate of uptake of calcium into the SR.An increase in contractility is accompanied by a shift of the ventricular function curve upward and to the left (greater stroke work at any level of ventricular end-diastolic pressure, or lower end-diastolic volume at any level of stroke work), whereas a shift downward and to the right characterizes depression of contractility (Fig. 265e-8). CHAPTER 265e Basic Biology of the Cardiovascular System Pattern of contraction FIGURE 265e-6 Signal systems involved in positive inotropic and lusitropic (enhanced relaxation) effects of β-adrenergic stimulation. When the β-adrenergic agonist interacts with the β receptor, a series of G protein–mediated changes leads to activation of adenylyl cyclase and the formation of cyclic adenosine monophosphate (cAMP). The latter acts via protein kinase A to stimulate metabolism (left) and phosphorylate the Ca2+ channel protein (right). The result is an enhanced opening probability of the Ca2+ channel, thereby increasing the inward movement of Ca2+ ions through the sarcolemma (SL) of the T tubule. These Ca2+ ions release more calcium from the sarcoplasmic reticulum (SR) to increase cytosolic Ca2+ and activate troponin C. Ca2+ ions also increase the rate of breakdown of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and inorganic phosphate (Pi). Enhanced myosin ATPase activity explains the increased rate of contraction, with increased activation of troponin C explaining increased peak force development. An increased rate of relaxation results from the ability of cAMP to activate as well the protein phospholamban, situated on the membrane of the SR, that controls the rate of uptake of calcium into the SR. The latter effect explains enhanced relaxation (lusitropic effect). P, phosphorylation; PL, phospholamban; TnI, troponin I.Philadelphia, Lippincott, Williams & Wilkins, 2004.Reprinted with permission.Copyright LH Opie, 2004.)The Ca2+ released from the SR then diffuses toward the myofibrils, where, as already described, it combines with troponin C (Fig.265e-6).By repressing this inhibitor of contraction, Ca2+ activates the myofilaments to shorten.
The tendon crosses immediately anterior to the joint capsule of the glenohumeral joint.7.45 and 7.46).It originates from, and fills, the subscapular fossa and inserts on the lesser tubercle of the humerus (Figs.The subscapularis muscle forms the largest component of the posterior wall of the axilla.This nerve is the lateral cutaneous branch of the second intercostal nerve (anterior ramus of T2). It communicates with a branch of the brachial plexus (the medial cutaneous nerve of the arm) in the axilla and supplies skin on the upper posteromedial side of the arm, which is part of the T2 dermatome. The lateral wall of the axilla is narrow and formed entirely by the intertubercular sulcus of the humerus (Fig. 7.44). The pectoralis major muscle of the anterior wall attaches to the lateral lip of the intertubercular sulcus. The latissimus dorsi and teres major muscles of the posterior wall attach to the floor and medial lip of the intertubercular sulcus, respectively (Table 7.5). The posterior wall of the axilla is complex (Fig. 7.45 and see Fig. 7.50). Its bone framework is formed by the costal surface of the scapula. Muscles of the wall are: the subscapularis muscle (associated with the costal surface of the scapula), the distal parts of the latissimus dorsi and teres major muscles (which pass into the wall from the back and posterior scapular region), and the proximal part of the long head of the triceps brachii muscle (which passes vertically down the wall and into the arm). Gaps between the muscles of the posterior wall form apertures through which structures pass between the axilla, posterior scapular region, and posterior compartment of the arm. The subscapularis muscle forms the largest component of the posterior wall of the axilla. It originates from, and fills, the subscapular fossa and inserts on the lesser tubercle of the humerus (Figs. 7.45 and 7.46). The tendon crosses immediately anterior to the joint capsule of the glenohumeral joint.The subscapularis is innervated by branches of the brachial plexus (the superior and inferior subscapular nerves), which originate in the axilla.The inferolateral aspect of the posterior wall of the axilla is formed by the terminal part of the teres major muscle and the tendon of the latissimus dorsi muscle (Fig.7.45).