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Variations in the apolipoprotein E (ApoE) gene have strong associations with Alzheimer’s disease in the HIV-uninfected population.Hiv-associated neurocognitive disorder HIV-associated neurocognitive disorder (HAND) comprises a spectrum of neurocognitive deficits due to HIV infection.The mechanisms by which MYH9/APOL1 variants predispose to HIVAN are currently unknown.The mechanism associated with the SNP in PSORS1C3 is unknown. GWAS in African Americans identified a SNP that tags the HLA-B*57:03 allele that is known to associate with lower virologic setpoint and slower disease course. Together these GWAS data underscore the importance of variations in HLA class I loci in control of viral replication. GENETIC ASSOCIATIONS WITH SPECIFIC AIDS AND NON-AIDS CONDITIONS • carotid artery disease Many of the non-AIDS events in HIV-infected individuals resemble those related to immune senescence and those found in the HIV-uninfected aging population. A functional SNP in the ryanodine receptor 3 (RYR3) gene was found to be associated with an increased risk of common carotid intima–media thickness (cIMT), which is a surrogate for subclinical atherosclerosis. Functional studies on RYR3 and its isoforms demonstrate a major role of these receptors in modulating endothelial function and atherogenesis via calcium signaling pathways, providing a biologically plausible mechanism by which the SNP in RYR3 may associate with increased cIMT risk. renal disease HIV-1-associated nephropathy (HIVAN) is a form of focal sclerosing glomerulonephritis caused by direct infection of kidney epithelial cells with HIV. HIVAN is more common in persons of African descent. There is evidence that polymorphisms in the MYH9 gene and in the neighboring APOL1 gene are a strong determinant of susceptibility to HIVAN in African Americans. The effect of carrying two APOL1 risk alleles explains nearly 35% of HIVAN. The mechanisms by which MYH9/APOL1 variants predispose to HIVAN are currently unknown. Hiv-associated neurocognitive disorder HIV-associated neurocognitive disorder (HAND) comprises a spectrum of neurocognitive deficits due to HIV infection. Variations in the apolipoprotein E (ApoE) gene have strong associations with Alzheimer’s disease in the HIV-uninfected population.Macrophage recruitment and activation plays a central role in the development of many of the HAND syndromes.Variations in chemokines that play an influential role in macrophage activation and recruitment, namely CCL2 (MCP-1) and CCL3 (MIP-1α), have been shown to alter the risk of developing HAND.Variations in mitochondrial genes also have been associated with risk of AIDS and HAND. |
Consideration of the mechanism of immediate-type hypersensitivity diseases in the human has focused largely on the IgE-dependent recognition of otherwise innocuous substances.An additional recently activating factor; PGD2, prostaglandin D2; TNF, tumor necrosis factor. recognized class of c-kit-expressing innate cells chemokines. Bronchial biopsy specimens from patients with asthma 2115 reveal that mast cells are immunohistochemically positive for IL-4 and IL-5, but that the predominant localization of IL-4, IL-5, and GM-CSF is to T cells, defined as TH2 by this profile. IL-4 modulates the T cell phenotype to the TH2 subtype, determines the isotype switch to IgE (as does IL-13), and upregulates FcεRI-mediated expression of cytokines by mast cells based on in vitro studies. An immediateandlate cellular phase ofallergicinflammation can be induced in the skin, nose, or lung of some allergic humans with local allergen challenge. The immediate phase in the nose involves pruritus and waterydischarge; in the lung, it involves bronchospasm and mucus secretion; and in the skin, it involves a wheal-and-flare response with pruritus. The reduced nasal patency, reduced pulmonary function, or erythema with swelling at the skin site in a late-phase response at 6–8 h is associated with biopsy findings of infiltrating and activated TH2 cells, eosinophils, basophils, and some neutrophils. The progression from early mast cell activation to late cellular infiltration has been used as an experimentalsurrogateofrhinitisorasthma.However,inasthma,there is an intrinsic hyperreactivity of the airways independent of the associated inflammation. Moreover, early-and late-phase responses (at least in the lung) are far more sensitive to blockade of IgE-dependent mast cell activation (or actions of histamine and cysteinyl leukotrienes) than are spontaneous or virally induced asthma exacerbations. Consideration of the mechanism of immediate-type hypersensitivity diseases in the human has focused largely on the IgE-dependent recognition of otherwise innocuous substances.Genes with linkage to the specific IgE response to particular allergens include those encoding the major histocompatibility complex (MHC) and certain chains of the T cell receptor (TCR-αδ). |
The higher the radiation doses, the shorter and more severe each stage.In addition, ARS exists in four stages: prodrome, latent phase, clinical illness, and recovery or death.ARS manifests as three major groups of signs and symptoms: hematopoietic, gastrointestinal, and neurovascular.The LD50/30 (i.e., the dose that causes a 50% mortality rate at 30 days) is ~4 Gy for whole-body exposure without medical support; with medical support, the LD ranges between 8 and 10 Gy. On top of its immediate effects, a massive blast forms a crater in the soil and usually produces ground shock that compounds the physical damage and the number of casualties. Inhalation of large amounts of radioactive dust causes pneumonitis that can lead to pulmonary fibrosis. Use of a mask covering the mouth and nose can result in effective prevention. The intense flash of infrared and visible light can cause either temporary or permanent blindness. Cataracts can develop months to years later among survivors. Acute radiation syndrome (ARS) refers to multisystem symptomatology resulting hours to weeks after radiation exposure. As discussed earlier, cell sensitivity to radiation damage increases as the cell replication rate increases and as cell differentiation decreases. Bone marrow and mucosal surfaces of the gastrointestinal tract, which have vast mitotic activity, are significantly more sensitive to radiation than are slowly dividing tissues such as bones and muscles. After exposure of all or most of the human body to ionizing radiation, ARS can develop. The clinical manifestations of ARS reflect the dose and type of radiation as well as the parts of the body exposed. ARS manifests as three major groups of signs and symptoms: hematopoietic, gastrointestinal, and neurovascular. In addition, ARS exists in four stages: prodrome, latent phase, clinical illness, and recovery or death. The higher the radiation doses, the shorter and more severe each stage.At the end of the prodrome, ARS progresses to the latent phase.Minimal or no symptoms are present during the latent phase, which commonly lasts up to 2.5 weeks but can last up to 6 weeks.The duration depends on the radiation dose, the prior health of the patient, and coexisting illness or injury. |
A.These modifications may include removal of part of the translated sequence or the covalent addition of one or more chemical groups required for protein activity.CO-AND POSTTRANSLATIONAL MODIFICATIONS
Many polypeptides are covalently modified, either while they are still attached to the ribosome (cotranslational) or after their synthesis has been completed (posttranslational).VI.In both eukaryotes and prokaryotes, regulation can also be achieved through proteins that bind mRNA and inhibit its use by blocking translation. E. Protein folding
Proteins must fold to assume their functional, native state. Folding can be spontaneous (as a result of the primary structure) or facilitated by proteins known as chaperones (see p. 20). F. Protein targeting
Although most protein synthesis in eukaryotes is initiated in the cytoplasm, many proteins perform their functions within subcellular organelles or outside of the cell. Such proteins normally contain amino acid sequences that direct the proteins to their final locations. For example, secreted proteins are targeted during synthesis (cotranslational targeting) to the RER by the presence of an N-terminal hydrophobic signal sequence. The sequence is recognized by the signal recognition particle (SRP), a ribonucleoprotein that binds the ribosome, halts elongation, and delivers the ribosome–peptide complex to an RER membrane channel (the translocon) via interaction with the SRP receptor. Translation resumes, the protein enters the RER lumen, and its signal sequence is cleaved (Fig. 32.15). The protein moves through the RER and the Golgi, is processed, packaged into vesicles, and secreted. Proteins targeted after synthesis (posttranslational) include nuclear proteins that contain an internal, short, basic nuclear localization signal; mitochondrial matrix proteins that contain an N-terminal, amphipathic, α-helical mitochondrial entry sequence; and peroxisomal proteins that contain a C-terminal tripeptide signal. VI. CO-AND POSTTRANSLATIONAL MODIFICATIONS
Many polypeptides are covalently modified, either while they are still attached to the ribosome (cotranslational) or after their synthesis has been completed (posttranslational). These modifications may include removal of part of the translated sequence or the covalent addition of one or more chemical groups required for protein activity. A.Portions of the protein must be removed by specialized endoproteases, resulting in the release of an active molecule.The cellular site of the cleavage reaction depends on the protein to be modified.Some precursor proteins are cleaved in the RER or the Golgi; others are cleaved in developing secretory vesicles (for example, insulin; see Fig. |
These α motor neurons, in turn, synapse on skeletal muscle fibers.Motor centers in the brain control the activity of α motor neurons in the ventral horns of the spinal cord.Contraction of skeletal muscle is under control of the central nervous system (i.e., voluntary).2.Further increases in load result in stretching the muscle (negative velocity). The maximal isometric tension (i.e., force at which shortening velocity is zero) is proportional to the number of active cross-bridges between actin and myosin, and it is usually greater for fast-twitch motor units (because of the larger diameter of fast-twitch muscle fibers and greater number of muscle fibers in a typical fast-twitch motor unit). In
Fig. 12.24 , the power-stress curve reflects the rate of work done at each load and shows that the maximal rate of work was done at a submaximal load (namely, when the force of contraction was approximately 30% of the maximal tetanic tension). To calculate the latter curve, the x-and y-coordinates were simply multiplied, and then the product was plotted as a function of the x-coordinate. 1. Skeletal muscle is composed of numerous muscle cells (muscle fibers) that are typically 10 to 80 µm in diameter and up to 25 cm in length. The appearance of striations in skeletal muscle is due to the highly organized arrangement of thick and thin filaments in the myofibrils of skeletal muscle fibers. The sarcomere is a contractile unit in skeletal muscle. Each sarcomere is approximately 2 µm in length at rest and is bounded by two Z lines. Sarcomeres are arranged in series along the length of the myofibril. Thin filaments, containing actin, extend from the Z line toward the center of the sarcomere. Thick filaments, containing myosin, are positioned in the center of the sarcomere and overlap the actin thin filaments. Muscle contraction results from the Ca++-dependent interaction of myosin and actin, in which myosin pulls the thin filaments toward the center of the sarcomere. 2. Contraction of skeletal muscle is under control of the central nervous system (i.e., voluntary). Motor centers in the brain control the activity of α motor neurons in the ventral horns of the spinal cord. These α motor neurons, in turn, synapse on skeletal muscle fibers.A motor unit refers to all the muscle fibers innervated by a single motor neuron.3.The motor neuron initiates contraction of skeletal muscle by producing an action potential in the muscle fiber. |
The arm tends to assume a flexed adducted posture and the leg an extended one.Gradually spasticity develops, and the tendon reflexes become brisker.Characteristically, the paralyzed muscles are flaccid in the first days or weeks following a stroke; the tendon reflexes are usually unchanged but may be slightly increased or decreased.With other small infarcts, recovery may start within a day or two, and restoration may be complete or nearly complete within a week. In cases of severe deficit, there may be little significant recovery; after months of assiduous efforts at rehabilitation, the patient may remain bereft of speech and understanding, with the upper extremity still useless and the lower extremity serving only as an uncertain prop during attempts to walk. Between these two extremes there is every gradation of recovery. Measurement of central motor conduction by magnetic stimulation has been somewhat predictive of motor recovery but is not widely used for clinical work. If clinical recovery does not begin in 1 or 2 weeks, the outlook is poorer for both motor and language functions. Constructional apraxia, uninhibited anger (with left and rarely with right temporal lesions), nonsensical logorrhea and placidity, unawareness of the paralysis and neglect (with nondominant parietal lesions), and confusion and delirium (with nondominant temporal lesions) all tend to diminish and may disappear within a few weeks. A hemianopia that has not cleared in a few weeks will usually be permanent, although reading and color discrimination may continue to improve. In lateral medullary infarction, difficulty in swallowing may be protracted, lasting 8 weeks or longer, yet relatively normal function is finally restored in nearly every instance. Aphasia, dysarthria, cerebellar ataxia, and walking may improve for a year or longer, but for all practical purposes it may be said that whatever motor and language deficits remain after 5 to 6 months will be permanent. Characteristically, the paralyzed muscles are flaccid in the first days or weeks following a stroke; the tendon reflexes are usually unchanged but may be slightly increased or decreased. Gradually spasticity develops, and the tendon reflexes become brisker. The arm tends to assume a flexed adducted posture and the leg an extended one.Conversely, the early development of spasticity in the arm or the early appearance of a grasp reflex may presage a favorable outcome.In some patients with extensive temporoparietal lesions, the hemiplegia remains flaccid; the arm dangles and the slack leg must be braced to stand.The physiologic explanation of this remains obscure. |
Investigations are being undertaken with antiangiogenic antibodies for recurrent tumors.Conventional chemotherapy and hormonal therapy are probably ineffective, but the latter has been a subject of interest.On CT performed without contrast they are isodense or slightly hyperdense; calcification at the outer surface or heterogeneously throughout the mass is common. The amount of edema surrounding the tumor is highly variable and may relate to the extent of local brain symptoms. The CSF protein is usually elevated. Treatment Surgical excision should afford long-term or permanent cure in most symptomatic and accessible tumors. Recurrence is likely if removal is incomplete, as is often the case, but for some the growth rate is so slow that there may be a latency of many years or decades. A few tumors show malignant qualities; that is, a high mitotic index, nuclear atypia, marked nuclear and cellular pleomorphism, and invasiveness of brain. Their regrowth is then rapid if they are not completely excised. Tumors that lie beneath the hypothalamus, along the medial part of the sphenoid bone and parasellar region, or anterior to the brainstem are the most difficult to remove surgically. By invading adjacent bone, they may become impossible to remove totally. Carefully planned radiation therapy, including various forms of stereotactic treatment, is beneficial in cases that are inoperable and when the tumor is incompletely removed or shows malignant characteristics. Smaller tumors at the base of the skull can be obliterated or reduced in size by focused radiation, probably with comparable or less risk than posed by surgery (see discussion by Chang and Alder). Conventional chemotherapy and hormonal therapy are probably ineffective, but the latter has been a subject of interest. Investigations are being undertaken with antiangiogenic antibodies for recurrent tumors.There is a peak incidence in the fifth through seventh decades of life, or in the third and fourth decades in patients with AIDS and the incidence is increasing independent of this form of immunosuppression. |
The GABAB receptor is a metabotropic receptor.GABAC receptors are structurally similar to GABAA receptors but have a distinct pharmacological profile (e.g., they are not affected by benzodiazepines) and are coded for by a separate set of genes (ρ1, ρ2, and ρ3).Each variant results in a receptor having distinct conductance, kinetics, agonist and antagonist affinity, and modulatory sites. Intriguingly, subunit variants are differentially expressed during development and in different brain regions. GABA has two separate ionotropic receptors (GABAA and GABAC) coded for by distinct sets of genes. Like glycine receptors, both control a Cl− channel. GABAA receptors are heteromers generated from seven classes of subunits, three of which have multiple members. The most common configuration is α1, β2, γ2 in a 2:2:1 stoichiometry, which may account for 80% of the receptors; however, many other heteromers are found in the brain. As with glycine, different subunits confer distinct properties on the receptor. For example, GABAA receptors are the targets of two major classes of drugs: benzodiazepines and barbiturates. Benzodiazepines (e.g., diazepam) are widely used antianxiety and relaxant drugs. Barbiturates are used as sedatives and anticonvulsants. Both classes of drugs bind to distinct sites on the α subunits of GABAA receptors and enhance opening of the receptors’ Cl− channels in response to GABA. The sedative and anticonvulsant actions of benzodiazepines appear to be mediated by receptors with the α1 subunit, whereas the anxiolytic effects reflect binding to receptors with the α2 subunit. GABAC receptors are structurally similar to GABAA receptors but have a distinct pharmacological profile (e.g., they are not affected by benzodiazepines) and are coded for by a separate set of genes (ρ1, ρ2, and ρ3). The GABAB receptor is a metabotropic receptor.Excitatory Amino Acid Receptors: Glutamate
Glutamate has both ionotropic and metabotropic receptors.Based on pharmacological properties and subunit composition, several distinct ionotropic receptor subtypes are recognized: AMPA, kainate, and NMDA.Overall, there are 18 known genes that code for glutamate subunits for the ionotropic glutamate receptors. |
Am J Obstet Gynecol 1992;166:17–28, with permission.)Anatomic aspects of vaginal eversion after hysterectomy.(Modified from DeLancey JOL.Figure 5.23 DeLancey levels of support.Level III support consists of the distal vaginal attachments: anteriorly, via fusion of the urethra to the vagina, laterally, to the levators, and posteriorly, with the perineal body.Laterally, endopelvic fascial condensations attach the midvagina to the pelvic walls at the arcus tendineus fascia pelvis anteriorly and the arcus tendineus levator ani posteriorly. The distal anterior vagina and urethra are anchored to the urogenital diaphragm and the distal posterior vagina to the perineal body. Anteriorly, the pubourethral ligaments and pubovesical fascia and ligaments provide fixation and stabilization for the urethra and bladder. Posteriorly, they rely on the vagina and lower uterus for support. Partial resection or relaxation of the uterosacral ligaments often leads to relaxation of the genitourinary complex, resulting in the formation of a cystocele. Studies indicate that half of the observed variation in anterior compartment support may be explained by apical support (39). Various types and degrees of genital tract prolapse or relaxation are almost always associated with similar findings in the bladder, urethra, or both. There are three levels of vaginal support as described by DeLancey (Fig. 5.23) (40). Level I support consists of paracolpium that suspends the apical portion of the vagina and is comprised of the cardinal-uterosacral ligament complex. Level II support comprises the paracolpium that is attached to the vagina laterally via the arcus tendineus fasciae pelvis and superior fascia of the levator ani. Level III support consists of the distal vaginal attachments: anteriorly, via fusion of the urethra to the vagina, laterally, to the levators, and posteriorly, with the perineal body. Figure 5.23 DeLancey levels of support. (Modified from DeLancey JOL. Anatomic aspects of vaginal eversion after hysterectomy. Am J Obstet Gynecol 1992;166:17–28, with permission.)All levels of defective support should be repaired during reconstructive surgery.Blood Supply The blood supply to the vulva is as follows: 1.External pudendal artery (from femoral artery), internal pudendal artery 2.The blood supply to the superficial and deep perineal compartments is as follows: 1.Internal pudendal artery, dorsal artery of the clitoris 2. |
(Anaplasia refers to the more primitive undifferentiated state of the constituent cells.)A normal astrocyte, oligodendrocyte, microgliocyte, or ependymocyte is transformed into a neoplastic cell and, as it multiplies, the daughter cells become variably anaplastic, more so as the degree of malignancy increases.The difficulty one encounters in distinguishing it from a true neoplasm, whose constituent cells multiply without restraint, is well illustrated by tuberous sclerosis and von Recklinghausen neurofibromatosis, where hamartomas and neoplasms are both found. Similarly, in a number of mass lesions—such as certain cerebellar astrocytomas, bipolar astrocytomas of the pons and optic nerves, von Hippel-Lindau cerebellar cysts, and pineal teratomas—a clear distinction between neoplasms and hamartomas is often not possible. The understanding of the pathogenesis of brain tumors has evolved greatly. Johannes Müller (1838), in his atlas Structure and Function of Neoplasms, first enunciated the appealing idea that tumors might originate in embryonic cells left in the brain during development. This idea was elaborated upon by Cohnheim in 1878, who postulated that the source of tumors was an anomaly of the embryonic anlage. Ribbert, in 1904, extended this hypothesis by postulating that the potential for differentiation of these stem cells would favor blastomatous growth, an idea that has now been resurrected. For many years, thinking about the pathogenesis of primary CNS tumors was dominated by the histogenetic theory of Bailey and Cushing, which was based on the assumed embryology of nerve and glia cells. Although it is no longer held to be valid, Bailey and Cushing attached the suffix blastoma to indicate all tumors composed of primitive-looking cells, such as glioblastoma and medulloblastoma. One prominent theory was that most tumors arise from neoplastic transformation of mature adult cells (dedifferentiation). A normal astrocyte, oligodendrocyte, microgliocyte, or ependymocyte is transformed into a neoplastic cell and, as it multiplies, the daughter cells become variably anaplastic, more so as the degree of malignancy increases. (Anaplasia refers to the more primitive undifferentiated state of the constituent cells.)If this is indeed the case, it may be that the apparent dedifferentiation of both the cells of origin and of tumor cells is not a fundamental property of brain tumors.The factor of age plays a central role in the biology of brain tumors. |
New mutations do not appear to contribute to the pool of affected individuals.DM1 and DM2 are both autosomal dominant disorders.Necrosis of muscle fibers and increased connective tissue, common in other muscular dystrophies, are less apparent in myotonic dystrophy.Mitral valve prolapse also occurs commonly. Other associated features include intellectual impairment, hypersomnia, posterior subcapsular cataracts, gonadal atrophy, insulin resistance, and decreased esophageal and colonic motility. Congenital myotonic dystrophy is a more severe form of DM1 and occurs in ~25% of infants of affected mothers. It is characterized by severe facial and bulbar weakness, transient neonatal respiratory insufficiency, and mental retardation. DM2, or PROMM, has a distinct pattern of muscle weakness affecting mainly proximal muscles. Other features of the disease overlap with DM1, including cataracts, testicular atrophy, insulin resistance, constipation, hypersomnia, and cognitive defects. Cardiac conduction defects occur but are less common, and the hatchet face and frontal baldness are less consistent features. A very striking difference is the failure to clearly identify a congenital form of DM2. Laboratory Features The diagnosis of myotonic dystrophy can usually be made on the basis of clinical findings. Serum CK levels may be normal or mildly elevated. EMG evidence of myotonia is present in most cases of DM1 but may be more patchy in DM2. Muscle biopsy shows muscle atrophy, which selectively involves type 1 fibers in 50% of cases, and ringed fibers in DM1 but not in DM2. Typically, numerous internalized nuclei can be seen in individual muscle fibers as well as atrophic fibers with pyknotic nuclear clumps in both DM1 and DM2. Necrosis of muscle fibers and increased connective tissue, common in other muscular dystrophies, are less apparent in myotonic dystrophy. DM1 and DM2 are both autosomal dominant disorders. New mutations do not appear to contribute to the pool of affected individuals.An increase in the severity of the disease phenotype in successive generations (genetic anticipation) is accompanied by an increase in the number of trinucleotide repeats.A similar type of mutation has been identified in fragile X syndrome (Chap.451e).The unstable triplet repeat in myotonic dystrophy can be used for prenatal diagnosis. |
The inclusion of a chapter on obsessive-compulsive and related disorders in DSM-5 re- flects the increasing evidence of these disorders’ relatedness to one another in terms of a range of diagnostic validators as well as the clinical utility of grouping these disorders in the same chapter.The unspecified anxiety disorder cate- gory is used in situations in which the clinician chooses not to specify the reason that the criteria are not met for a specific anxiety disorder, and includes presentations in which there is insufficient information to make a more specific diagnosis (e.g., in emergency room settings). .. r.,,__.... .0. W .._,. W disorder (OCD), body dysmorphic disorder, hoarding disorder, trichotillomania (hair- pulling disorder), excoriation (skin—picking) disorder, substance/medication-induced ob- sessive-compulsive and related disorder, obsessive-compulsive and related disorder due to another medical condition, and other specified obsessive—compulsive and related dis— order and unspecified obsessive-compulsive and related disorder (e.g., body-focused re- petitive behavior disorder, obsessional jealousy). OCD is characterized by the presence of obsessions and / or compulsions. Obsessions are recurrent and persistent thoughts, urges, or images that are experienced as intrusive and unwanted, whereas compulsions are repetitive behaviors or mental acts that an indi- vidual feels driven to perform in response to an obsession or according to rules that must be applied rigidly. Some other obsessive-compulsive and related disorders are also char- acterized by preoccupations and by repetitive behaviors or mental acts in response to the preoccupations. Other obsessive-compulsive and related disorders are characterized pri- marily by recurrent body-focused repetitive behaviors (e.g., hair pulling, skin picking) and repeated attempts to decrease or stop the behaviors. The inclusion of a chapter on obsessive-compulsive and related disorders in DSM-5 re- flects the increasing evidence of these disorders’ relatedness to one another in terms of a range of diagnostic validators as well as the clinical utility of grouping these disorders in the same chapter.At the same time, there are important differences in diagnostic validators and treatment ap- proaches across these disorders. |
During grimacing in response to stimuli, facial weakness may be noted.A moan or grimace may be provoked by painful stimuli applied to one side but not to the other, reflecting hemianesthesia.Resistance to movement of the neck in all directions may be part of generalized muscular rigidity or dystonia or indicate disease of the cervical spine. In the infant, bulging of the anterior fontanel is at times a more reliable sign of meningitis than is a stiff neck. A temporal lobe or cerebellar herniation or decerebrate rigidity may also create resistance to passive flexion of the neck and be confused with meningeal irritation. A coma-causing lesion in a cerebral hemisphere can be detected by careful observation of spontaneous movements, responses to stimulation, prevailing postures, and by examination of the cranial nerves. Hemiplegia is revealed by a lack of restless movements of the limbs on one side and by inadequate protective movements in response to painful stimuli. The weakened limbs are usually slack and, if lifted from the bed, they “fall flail.” The hemiplegic leg lies in a position of external rotation (this may also be caused by a fractured femur), and the affected thigh appears wider and flatter than the nonhemiplegic one. In expiration, the cheek and lips puff out on the paralyzed side of the face. A lesion in one cerebral hemisphere causes the eyes to be turned away from the paralyzed side (toward the lesion, as described below); the opposite occurs with brainstem lesions. In most cases, a hemiplegia and an accompanying Babinski sign are indicative of a contralateral hemispheral lesion; but with lateral mass effect and compression of the opposite cerebral peduncle against the tentorium, extensor posturing, a Babinski sign, and weakness of arm and leg may appear ipsilateral to the lesion (the earlier-mentioned Kernohan-Woltman sign). A moan or grimace may be provoked by painful stimuli applied to one side but not to the other, reflecting hemianesthesia. During grimacing in response to stimuli, facial weakness may be noted.These functions, like consciousness itself, are dependent on the integrity of structures in the midbrain and rostral pons.These are of great diagnostic importance in the comatose patient. |
Approximately 5% to 7% of carotid body tumors are malignant.Tumors involving these structures have been referred to as paraganglioma, glomus tumor, or chemo-dectoma.Other glands of neural crest origin are seen in Brunicardi_Ch23_p0897-p0980.indd 91827/02/19 4:14 PM 919ARTERIAL DISEASECHAPTER 23the neck, parapharyngeal spaces, mediastinum, retroperitoneum, and adrenal medulla.Patients typically present with a pul-satile neck mass. The available data suggest that, untreated, these aneurysms lead to neurologic symptoms from emboliza-tion. Thrombosis and rupture of the carotid aneurysm are rare. Pseudoaneurysms of the carotid artery can result from injury or infection. Mycotic aneurysms often involved syphilis in the past, but they are now more commonly associated with peri-tonsillar abscesses caused by Staphylococcus aureus infection. FMD and spontaneous dissection of the carotid artery can lead to A B CA BFigure 23-27. A. A carotid body tumor (arrow) located adjacent to the carotid bulb. B. Following periad-ventitial dissection, the carotid body tumor is removed.the formation of true aneurysms or pseudoaneurysms. Whereas conventional surgery has been the primary mode of treatment in the past, carotid aneurysms are currently being treated more commonly using endovascular approaches.38Carotid Body Tumor. The carotid body originates from the third branchial arch and from neuroectodermal-derived neural crest lineage. The normal carotid body is located in the adven-titia or periadventitial tissue at the bifurcation of the common carotid artery (Fig. 23-27). The gland is innervated by the glos-sopharyngeal nerve. Its blood supply is derived predominantly from the external carotid artery but can also come from the ver-tebral artery. Carotid body tumor is a rare lesion of the neuroen-docrine system. Other glands of neural crest origin are seen in Brunicardi_Ch23_p0897-p0980.indd 91827/02/19 4:14 PM 919ARTERIAL DISEASECHAPTER 23the neck, parapharyngeal spaces, mediastinum, retroperitoneum, and adrenal medulla. Tumors involving these structures have been referred to as paraganglioma, glomus tumor, or chemo-dectoma. Approximately 5% to 7% of carotid body tumors are malignant.Patients usually present between the fifth and seventh decades of life with an asymptomatic lateral neck mass.The diagnosis of carotid body tumor requires confir-mation on imaging studies.Carotid duplex scan can localize the tumor to the carotid bifurcation, but CT or MRI is usually required to further delineate the relationship of the tumor to the adjacent structures. |
The characteristic shape, with the apical accumulation small intestine, goblet cells increase in number from the duo-of granules and the narrow basal stem, is responsible for the denum to the terminal part of the ileum.In the plasm.Mitochondria are also concentrated in the basal cyto-As in other epithelia, goblet cells produce mucus.somes.The characteristic complement of major organelles is depicted in the diagram. b. This cell shows the distribution of lipid during fat absorption as seen with the TEM. Initially, lipids are seen in association with the microvilli of the striated border. Lipids are internalized and seen in vesicles of the smooth endoplasmic reticulum (sER) in the apical portion of the cell. The membrane-bounded lipid can be traced to the center of the cell, where many of the lipid-containing vesicles fuse. The lipid is then discharged into the intercellular space. The extracellular lipids, recognized as chylomicrons, pass beyond the basal lamina for further transport into lymphatic (green) and/or blood vessels (red). glands. The secretion that occurs in these glands is thought ination with the TEM reveals a large accumulation of mu-to assist the process of digestion and absorption by maintain-cinogen granules in the apical cytoplasm that distends the ing an appropriate liquid state of the intestinal chyme. apex of the cell and distorts the shape of neighboring cells Under normal conditions, the absorption of fluid by the vil-(Fig. 17.22). With the apex of the cell containing a large lus enterocyte is balanced by the secretion of fluid by the accumulation of mucinogen granules, the basal portion of the gland enterocyte. cell resembles a narrow stem. This basal portion is intensely basophilic in histologic preparations because it is occupied by
Goblet cells represent unicellular glands that are inter- a heterochromatic nucleus, extensive rER, and free ribo spersed among the other cells of the intestinal epithelium. somes. Mitochondria are also concentrated in the basal cyto-As in other epithelia, goblet cells produce mucus. In the plasm. The characteristic shape, with the apical accumulation small intestine, goblet cells increase in number from the duo-of granules and the narrow basal stem, is responsible for the denum to the terminal part of the ileum.Exam-cell (see Fig.17.22a).The microvilli of goblet cells are
FIGURE 17.22 • Electron micrograph and the diagram of a goblet cell.a.This electron micrograph shows the basal portion of a goblet cell depicted on the adjacent diagram.The cell rests on the basal lamina.The basal portion of the cell contains the nucleus, rough endoplasmic reticulum, and mitochondria. |
Even if the chemical structure of a drug allowed it to bind to only one kind of receptor, the biochemical processes controlled by such receptors would take place in many cell types and would be coupled to many other biochemical functions; as a result, the patient and the prescriber would probably perceive more than one drug effect.Before initiating therapy with a drug, the prescriber should be aware of patient characteristics that may limit the clinical response. These characteristics include the age and general health of the patient and—most importantly—the severity and pathophysiologic mechanism of the disease. The most important potential cause of failure to achieve a satisfactory response is that the diagnosis is wrong or physiologically incomplete. Drug therapy is most successful when it is accurately directed at the pathophysiologic mechanism responsible for the disease. When the diagnosis is correct and the drug is appropriate, an unsatisfactory therapeutic response can often be traced to compensatory mechanisms in the patient that respond to and oppose the beneficial effects of the drug. Compensatory increases in sympathetic nervous tone and fluid retention by the kidney, for example, can contribute to tolerance to antihypertensive effects of a vasodilator drug. In such cases, additional drugs may be required to achieve a useful therapeutic result. Clinical Selectivity: Beneficial versus Toxic Effects of Drugs
Although we classify drugs according to their principal actions, it is clear that no drug causes only a single, specific effect. Why is this so? It is exceedingly unlikely that any kind of drug molecule will bind to only a single type of receptor molecule, if only because the number of potential receptors in every patient is astronomically large. Even if the chemical structure of a drug allowed it to bind to only one kind of receptor, the biochemical processes controlled by such receptors would take place in many cell types and would be coupled to many other biochemical functions; as a result, the patient and the prescriber would probably perceive more than one drug effect.It is only because of their selectivity that drugs are useful in clinical medicine.Selectivity can be measured by comparing binding affinities of a drug to different receptors or by comparing ED50s for different effects of a drug in vivo. |
Although this most commonly happens as a consequence of acute plaque change ( described next), it can also occur gradually, with critical stenosis being the tipping point at which chronic occlusion limits flow so severely
Fig.Owing to limits on remodeling, however, eventually the expanding atheroma may impinge on blood flow.Atheroembolism. Ruptured plaque can discharge debris into the blood, producing microemboli composed of plaque contents. Aneurysm formation. Atherosclerosis-induced pressure or ischemic atrophy of the underlying media, with loss of elastic tissue, causes structural weakening that can lead to aneurysmal dilation and rupture. Large elastic arteries (e.g., aorta, carotid, and iliac arteries) and largeand medium-sized muscular arteries (e.g., coronary, renal, and popliteal arteries) are the vessels most commonly involved by atherosclerosis. Accordingly, atherosclerosis is most likely to present with signs and symptoms related to ischemia of the heart, brain, kidneys, and lower extremities. Myocardial infarction (heart attack), cerebral infarction (stroke), aortic aneurysm, and peripheral vascular disease (gangrene of extremities) are the major clinical consequences of atherosclerosis. The natural history, morphologic features, and main pathogenic events are schematized in
Figure 10.15 . The principal pathophysiologic outcome stemming from atherosclerotic lesions vary depending on the size of the affected vessel, the size and stability of the plaques, and the degree to which plaques disrupt the vessel wall. We next describe the features of atherosclerotic lesions that are typically responsible for the clinical manifestations. At early stages, remodeling of the media tends to preserve the luminal diameter by increasing the overall vessel circumference. Owing to limits on remodeling, however, eventually the expanding atheroma may impinge on blood flow. Although this most commonly happens as a consequence of acute plaque change ( described next), it can also occur gradually, with critical stenosis being the tipping point at which chronic occlusion limits flow so severely
Fig.(B, Reproduced from Schoen FJ: Interventionalandsurgicalcardiovascularpathology:clinicalcorrelationsandbasicprinciples,Philadelphia, 1989, Saunders, p 61.) |
At puberty, under the influence of pituitary gonadotropins, the ovaries begin to undergo the cyclical changes designated the ovarian cycle.The oogonia in these follicles are arrested in prophase of the first meiotic division.In the cortex are numerous primordial follicles that are present at the time of birth and that remain unchanged until sexual maturation.In cultures in which breast-feeding may continue
The arteries that supply the breast are derived from the thoracic branches of the axillary artery, the internal thoracic artery, and anterior intercostal arteries. Branches of the vessels pass primarily along the path of the alveolar ducts as they reach capillary beds surrounding the alveoli. Veins basically follow the path of the arteries as they return to the axillary and internal thoracic veins. Lymphatic capillaries are located in the connective tissue surrounding the alveoli. The larger lymphatic vessels drain into axillary, supraclavicular, or parasternal lymph nodes. The nerves that supply the breast are anterior and lateral cutaneous branches from the second to sixth intercostal nerves. The nerves convey afferent and sympathetic fibers to and from the breast. The secretory function is primarily under hormonal control, but afferent impulses associated with suckling are involved in the reflex secretion of prolactin and oxytocin. This page intentionally left blank. The ovaries are small, paired, ovoid structures that exhibit a cortex and medulla when sectioned. On one side is a hilum for the transit of neu-rovascular structures; on this same side is a mesovarium that joins the ovary to the broad ligament. The functions of the ovary are the produc-tion of ova and the synthesis and secretion of estrogen and progesterone. In the cortex are numerous primordial follicles that are present at the time of birth and that remain unchanged until sexual maturation. The oogonia in these follicles are arrested in prophase of the first meiotic division. At puberty, under the influence of pituitary gonadotropins, the ovaries begin to undergo the cyclical changes designated the ovarian cycle.At the beginning of the ovarian cycle, under the influence of pituitary follicle-stimulating hormone (FSH), some of the primordial follicles begin to undergo changes that lead to the development of a mature (Graafian) follicle.These changes include a proliferation of follicular cells and enlargement of the follicle. |
38).A different dominantly inherited distal dystrophy was described by Welander in a study of 249 patients from 72 Swedish pedigrees (not to be confused with the
Kugelberg-Welander juvenile spinal muscular atrophy affecting proximal muscles; see Chap.Several types of distal dystrophies are inherited as autosomal dominant traits.Onset in infancy, ptosis, weakness of facial, jaw, and distal limb muscles, and mental abnormalities were notably absent, further distinguishing PROMM from the conventional (DM1) form of myotonic dystrophy. Histologically, there are many fibers with multiple (5 to 10 or more) internalized nuclei, without ringbinden or subsarcolemmal masses. In addition, there are atrophic fibers with nuclear clumps. Analysis of leukocyte and muscle DNA discloses no expansion of the CTG component of the myotonic dystrophy gene. Rather, the gene defect for this disease has been mapped to the CNBP gene on chromosome 3q where there is an expansion of a CCTG repeats. Like the expanded CTG repeat in myotonic dystrophy, the CCTG expansion in PROMM is associated with intranuclear accumulation of the expanded RNA transcript, and like the CTG repeats of myotonic dystrophy, the CCTG segments do not code for a protein. Distal Muscular Dystrophies (Welander, Miyoshi, and Other Types) (See Table 45-3)
Included in this group are several slowly progressive distal myopathies with onset principally in adult life. Weakness and wasting of the muscles of the hands, forearms, and lower legs, especially the extensors, are the main clinical features. Although such cases had been reported by Gowers and others, their differentiation from myotonic dystrophy and peroneal muscular atrophy was unclear until relatively recently. Several types of distal dystrophies are inherited as autosomal dominant traits. A different dominantly inherited distal dystrophy was described by Welander in a study of 249 patients from 72 Swedish pedigrees (not to be confused with the
Kugelberg-Welander juvenile spinal muscular atrophy affecting proximal muscles; see Chap. 38).Fasciculations, cramps, pain, sensory disturbances, and myotonia were notably absent.Some patients have a low-grade sensory neuropathy, suggesting that pathology in this disorder may not be exclusively in muscle.Cataracts appeared after the age of 70 years in 3 patients and can be discounted as having special significance.No endocrine disorders were detected. |
Even when administered by aerosol, the bronchodilation achievable with atropine, the prototypic muscarinic antagonist, is limited by absorption into the circulation and across the blood-brain barrier.Antimuscarinic agents are effective bronchodilators.However, the efficacy and safety of other drugs, especially inhaled β2agonists and inhaled corticosteroids, and the toxicities and need for monitoring of blood concentration of theophylline have made it almost obsolete in asthma treatment. Observation of the use of leaves from Datura stramonium for asthma treatment in India led to the discovery of atropine, a potent competitive inhibitor of acetylcholine at postganglionic muscarinic receptors, as a bronchodilator. Interest in the potential value of antimuscarinic agents increased with demonstration of the importance of the vagus nerves in bronchospastic responses of laboratory animals and with the development of ipratropium, a potent atropine analog that is poorly absorbed after aerosol administration and is therefore relatively free of systemic atropine-like effects. Mechanism of Action
Muscarinic antagonists competitively inhibit the action of acetylcholine at muscarinic receptors and are therefore sometimes referred to as “anticholinergic agents” (see Chapter 8). In the airways, acetylcholine is released from efferent endings of the vagus nerve, and muscarinic antagonists block the contraction of airway smooth muscle and the increase in secretion of mucus that occurs in response to vagal activity (Figure 20–6). This selectivity of muscarinic antagonists accounts for their usefulness as investigative tools to examine the role of parasympathetic reflex pathways in bronchomotor responses but limits their usefulness in preventing bronchospasm. In the doses given, antimuscarinic agents inhibit only that portion of the response mediated by muscarinic receptors, which varies by stimulus and which further appears to vary among individual responses to the same stimulus. Antimuscarinic agents are effective bronchodilators. Even when administered by aerosol, the bronchodilation achievable with atropine, the prototypic muscarinic antagonist, is limited by absorption into the circulation and across the blood-brain barrier.The airway is represented microscopically by a cross-section of the wall with branching vagal sensory endings lying adjacent to the lumen.Afferent pathways in the vagus nerves travel to the central nervous system; efferent pathways from the central nervous system travel to efferent ganglia. |
This nomenclature, based mainly on the clinical form of the seizure, and its EEG features, has been adopted worldwide and is generally referred to as the “International Classification.” A modified version of it is reproduced in Table 15-1.A distinction must be made between the classification of seizures: generalized tonic clonic (grand mal), absence (petit mal), myoclonic, partial, and others, and the classification of the epilepsies, or epileptic syndromes, which are specific diseases, many of which may manifest several seizure types. These are discussed later in the chapter. A further distinction is made by clinical and EEG features. This approach allows for the reasonable predictability of response to specific medications and to some extent, in prognosis. Basically, this classification divides seizures into two types—focal (formerly termed partial), in which a focal or localized onset can be discerned clinically or by EEG, or generalized, in which the seizures appear to begin bilaterally. Generalized seizures are of two types—convulsive and nonconvulsive. The common convulsive type is the tonic-clonic (grand mal) seizure. Less common is a purely tonic, purely clonic, atonic, and myoclonic. The typical nonconvulsive generalized seizure is the brief lapse of consciousness or absence (petit mal); included also under this heading are minor motor phenomena. Focal seizures can also be convulsive or uncommonly, nonconvulsive. Furthermore, focal seizures can secondarily generalize into any of the types listed above. The classification followed here was first proposed by Gastaut et al in 1970 and has been refined repeatedly by the Commission on Classification and Terminology of the International League against Epilepsy. This nomenclature, based mainly on the clinical form of the seizure, and its EEG features, has been adopted worldwide and is generally referred to as the “International Classification.” A modified version of it is reproduced in Table 15-1.In reality, an aura represents the initial phase of a focal seizure; in some instances, it may constitute the entire epileptic attack.A complementary classification is provided by considering the epilepsy syndromes, a group of somewhat diverse, age-dependent and usually genetically determined entities that arise without underlying structural abnormalities. |
The first step in the synthesis is the secretion of triglyceride-rich very-low-density lipoprotein (VLDL) by the liver into the blood.7.1 ).The endogenous synthesis of cholesterol and LDL begins in the liver (
Fig.Some of the cholesterol enters the metabolic pool (to be described), and some is excreted as free cholesterol or as bile acids into the biliary tract.Familial hypercholesterolemia is a “receptor disease” caused by loss-of-function mutations in the gene encoding the LDL receptor, which is involved in the transport and metabolism of cholesterol. As a consequence of receptor abnormalities there is a loss of feedback control that normally holds cholesterol synthesis in check. The resulting elevated levels of cholesterol induce premature atherosclerosis and greatly increase the risk of myocardial infarction. Familial hypercholesterolemia is among the most common of mendelian disorders; the frequency of the heterozygous condition is 1 in 500 in the general population. Approximately 7% of the body’s cholesterol circulates in the plasma, predominantly in the form of LDL. As might be expected, the amount of plasma cholesterol is influenced by its synthesis and catabolism, and the liver plays a crucial role in both these processes, as described later. A brief review of the synthesis and transport of cholesterol follows. Normal Cholesterol Metabolism. Cholesterol may be derived from the diet or from endogenous synthesis. Dietary triglycerides and cholesterol are incorporated into chylomicrons in the intestinal mucosa and travel by way of the gut lymphatics to the blood. These chylomicrons are hydrolyzed by an endothelial lipoprotein lipase in the capillaries of muscle and fat. The chylomicron remnants, rich in cholesterol, are then delivered to the liver. Some of the cholesterol enters the metabolic pool (to be described), and some is excreted as free cholesterol or as bile acids into the biliary tract. The endogenous synthesis of cholesterol and LDL begins in the liver (
Fig. 7.1 ). The first step in the synthesis is the secretion of triglyceride-rich very-low-density lipoprotein (VLDL) by the liver into the blood.In comparison with VLDL, the content of triglyceride is reduced and that of cholesteryl esters is enriched in IDL, but IDL retains on its surface the VLDL-associated apolipoproteins B-100 and E. Further metabolism of IDL occurs along two pathways: Most of the http://ebooksmedicine.net
Fig. |
The rate of cytologic abnormalities on Pap smear in pregnant women is about 5–8% and is not much different than the rate in nonpregnant women of the same age.Screening is recommended at the first prenatal visit and 6 weeks postpartum.Women generally tend to clear the infection by age 30, with the risk of cervical cancer being highest among those who fail to clear the infection.Pregnancy appears to have little or no impact on the natural history of malignancies, despite the hormonal influences. Spread of the mother’s cancer to the fetus (so-called vertical transmission) is exceedingly rare. The incidence of cervical cancer in pregnant women is roughly comparable to that of age-matched controls who are not pregnant. Invasive cervical cancer complicates about 0.45 in 1000 live births, and carcinoma in situ is seen in 1 in 750 pregnancies. About 1% of women diagnosed with cervical cancer are pregnant at the time of diagnosis. Early signs of cervical cancer include vaginal spotting or discharge, pain, and postcoital bleeding, which are also common features of pregnancy. Early visual changes in the cervix related to invasive cancer can be mistaken for cervical decidualization or ectropion (columnar epithelium on the cervix) due to pregnancy. Women diagnosed with cervical cancer during pregnancy report having had symptoms for 4.5 months on average. Approximately 95% of all cervical cancer is caused by human papillomavirus (HPV) infections, with types 16 and 18 accounting for about 70% of cervical cancer. The rate of carriage of these serotypes is highest among women in their early twenties and can be reduced with the use of vaccination before exposure. Women generally tend to clear the infection by age 30, with the risk of cervical cancer being highest among those who fail to clear the infection. Screening is recommended at the first prenatal visit and 6 weeks postpartum. The rate of cytologic abnormalities on Pap smear in pregnant women is about 5–8% and is not much different than the rate in nonpregnant women of the same age.Although the details of the recommendations for screening and management of abnormal results differ slightly among the three sets of guidelines, there is general consensus that cytology screening should start at age 21 and continue every 3 years through age 29.After age 30, cytology screening frequency may be reduced to every 5 years if accompanied by co-testing for HPV. |
It is a quantitative concept strictly dependent on dosage.The definition of a poison is not straightforward.We now consider some basic principles regarding the toxicity of exogenous chemicals and drugs.Of the approximately 100,000 chemicals in use in the United States, less than 1% have been tested experimentally for health effects.Approximately 10% of the world’s population—roughly 600 million people—live in low-lying areas that are at risk for flooding even if the rise in ocean levels is at the low end of these estimates. For example, a rise in sea level by 1.5 feet will submerge 70% of the land mass of Maldive islands by 2100 and a 3-foot rise will inundate 100% all of the islands by 2085. The resulting displacement of people will disrupt lives and commerce, creating conditions ripe for political http://ebooksmedicine.net unrest, war, and poverty, the “vectors” of malnutrition, sickness, and death. Worldwide recognition of the catastrophic effects of climate change led in late 2015 to a historic meeting of 196 countries in Paris, France, at which the participating countries agreed to the following objective:
Holding the increase in the global average temperature to well below 2°C above preindustrial levels and to pursue efforts to limit the temperature increase to 1.5°C above preindustrial levels, recognizing that this would significantly reduce the risks and impacts of climate change. Toxicology is defined as the science of poisons. It studies the distribution, effects, and mechanisms of action of toxic agents. More broadly, it also includes the study of the effects of physical agents such as radiation and heat. Approximately 4 billion pounds of toxic chemicals, including 72 million pounds of known carcinogens, are produced each year in the United States. In general, however, little is known about the potential health effects of chemicals. Of the approximately 100,000 chemicals in use in the United States, less than 1% have been tested experimentally for health effects. We now consider some basic principles regarding the toxicity of exogenous chemicals and drugs. The definition of a poison is not straightforward. It is a quantitative concept strictly dependent on dosage.Xenobiotics are exogenous chemicals in the environment that may be absorbed by the body through inhalation, ingestion, or skin contact (
Fig.8.2
Chemicals may be excreted in urine or feces or eliminated in expired air, or they may accumulate in bone, fat, brain, or other tissues.Chemicals may act at the site of entry, or they may be transported to other sites. |
N3 sleep is associated with secretion of growth hormone in men, while sleep in general is associated with augmented secretion of prolactin in both men and women.Endocrine function also varies with sleep.Decreases in minute ventilation during NREM sleep are out of proportion to the decrease in metabolic rate, resulting in a slightly higher Pco2.Formation of short-term memories is inhibited at the onset of NREM stage N1 sleep, which may explain why individuals aroused from that transitional sleep stage frequently lack situational awareness. After sleep deprivation, such transitions may intrude upon behavioral wakefulness notwithstanding attempts to remain continuously awake (see “Shift-Work Disorder,” below). Awakenings from REM sleep are associated with recall of vivid dream imagery over 80% of the time, especially later in the night. Imagery may also be reported after NREM sleep interruptions. Certain disorders may occur during specific sleep stages and are described below under “Parasomnias.” These include sleepwalking, night terrors, and enuresis (bed wetting), which occur most commonly in children during deep (N3) NREM sleep, and REM sleep behavior disorder, which occurs mainly among older men who fail to maintain full atonia during REM sleep, and often call out, thrash around, or even act out entire dreams. All major physiologic systems are influenced by sleep. Blood pressure and heart rate decrease during NREM sleep, particularly during N3 sleep. During REM sleep, bursts of eye movements are associated with large variations in both blood pressure and heart rate mediated by the autonomic nervous system. Cardiac dysrhythmias may occur selectively during REM sleep. Respiratory function also changes. In 187 comparison to relaxed wakefulness, respiratory rate becomes slower but more regular during NREM sleep (especially N3 sleep) and becomes irregular during bursts of eye movements in REM sleep. Decreases in minute ventilation during NREM sleep are out of proportion to the decrease in metabolic rate, resulting in a slightly higher Pco2. Endocrine function also varies with sleep. N3 sleep is associated with secretion of growth hormone in men, while sleep in general is associated with augmented secretion of prolactin in both men and women.Sleep onset (and probably N3 sleep) is associated with inhibition of thyroid-stimulating hormone and of the adrenocorticotropic hormone–cortisol axis, an effect that is superimposed on the prominent circadian rhythms in the two systems. |
Saliva includes the combined secretions of all the major and minor salivary glands.Some of the predominant mucous acini have serous de-milunes, but purely serous acini are rarely present.In the sublingual gland, however, the mucous acini predominate.The sublingual gland resembles the submandibular gland, in that it contains both serous and mu-cous elements.A cross-sectional profile of an intercalated duct (ID) appears on the left of the micrograph; note its simple cuboidal epithelium. A single flattened nucleus is present at the top of the duct and may represent one of the myoepithelial cells that are associated with the beginning of the duct system as well as with the acini (A). The large duct occupying the center of the micrograph is a striated duct (StD). It is composed of columnar epithelium. The striations (S) that give the duct its name are evident. Also of significance is the presence of plasma cells (PC) within the connective tissue surrounding the duct. These cells produce the immunoglobulins taken up and resecreted by the acinar cells, particularly secretory IgA (sIgA). PLATE 52 • PAROTI D G LAN D KEY A, acinus AC, adipose cell AL, acinar lumen CT, connective tissue ED, excretory duct ID, intercalated duct PC, plasma cells S, striations of duct cells StD, striated duct
The sublingual glands are the smallest of the paired major salivary glands. Their multiple small ducts empty into the submandibular ducts as well as directly onto the floor of the mouth. The sublingual gland resembles the submandibular gland, in that it contains both serous and mu-cous elements. In the sublingual gland, however, the mucous acini predominate. Some of the predominant mucous acini have serous de-milunes, but purely serous acini are rarely present. Saliva includes the combined secretions of all the major and minor salivary glands.Saliva is a source of calcium and phosphate ions essential for normal tooth development and maintenance.It also contains antibodies, no-tably salivary sIgA.Salivation is part of a reflex arc that is normally stimulated by the ingestion of food, although sight, smell, or even thoughts of food can also stimulate salivation.Sublingual gland, human, H&E ×160. |
B, Apple-green birefringence.A, Congo red.1.13 Amyloid.Fig.1.12 Fatty change of liver.Usually asymptomatic; present in 25% of individuals > 80 years of age
C. Familial amyloid cardiomyopathy
Fig.2.Non-mutated serum transthyretin deposits in the heart.B. Senile cardiac amyloidosis 1.LOCALIZED AMYLOIDOSIS
A. Amyloid deposition usually localized to a single organ.III.Amyloid cannot be removed.1.13)
C. Deposition can be systemic or localized. II. SYSTEMIC AMYLOIDOSIS
A. Amyloid deposition in multiple organs; divided into primary and secondary amyloidosis
B. Primary amyloidosis is systemic deposition of AL amyloid, which is derived from immunoglobulin light chain. 1. Associated with plasma cell dyscrasias (e.g., multiple myeloma)
C. Secondary amyloidosis is systemic deposition of AA amyloid, which is derived from serum amyloid-associated protein (SAA). 1. SAA is an acute phase reactant that is increased in chronic inflammatory states, malignancy, and Familial Mediterranean fever (FMF). 2. FMF is due to a dysfunction of neutrophils (autosomal recessive) and occurs in persons of Mediterranean origin. i. Presents with episodes of fever and acute serosal inflammation (can mimic appendicitis, arthritis, or myocardial infarction) ii. High SAA during attacks deposits as AA amyloid in tissues. D. Clinical findings of systemic amyloidosis are diverse since almost any tissue can be involved. Classic findings include 1. Nephrotic syndrome; kidney is the most common organ involved. 2. 3. Tongue enlargement, malabsorption, and hepatosplenomegaly
E. Diagnosis requires tissue biopsy. Abdominal fat pad and rectum are easily accessible biopsy targets. F. Damaged organs must be transplanted. Amyloid cannot be removed. III. LOCALIZED AMYLOIDOSIS
A. Amyloid deposition usually localized to a single organ. B. Senile cardiac amyloidosis 1. Non-mutated serum transthyretin deposits in the heart. 2. Usually asymptomatic; present in 25% of individuals > 80 years of age
C. Familial amyloid cardiomyopathy
Fig. 1.12 Fatty change of liver. Fig. 1.13 Amyloid. A, Congo red. B, Apple-green birefringence.Mutated serum transthyretin deposits in the heart leading to restrictive cardiomyopathy.2.5% of African Americans carry the mutated gene.D. Non-insulin-dependent diabetes mellitus (type II) 1.Amylin (derived from insulin) deposits in the islets of the pancreas.E. Alzheimer disease 1.AP amyloid (derived from P-amyloid precursor protein) deposits in the brain forming amyloid plaques.2. |
Early Machado-Joseph disease characteristically demonstrates the finding of dysmetric horizontal and vertical saccades, even before the ataxia is obvious (Hotson et al).There is usually no impairment of intellect and in the examples the authors have seen, the extrapyramidal symptoms were mainly rigidity and slowness of movement.This entity of MSA-C has been discussed with the degenerative disorders of the basal ganglia earlier in the chapter. Here it is pointed out that a number of cases of sporadic progressive ataxia in mid and late life are attributable to this process and have been termed MSA-C to signify the predominant cerebellar feature. The extrapyramidal, corticospinal, or autonomic aspects of the illness may or may not become evident with continued observation or by pathologic examination. Some guidance as to the frequency of MSA as the cause of otherwise undifferentiated sporadic ataxia is given in the study by Abele and colleagues who found that it accounts for almost one-third of cases, but the precise number is open to question as pathologic examinations were not made. Machado-Joseph-Azorean Disease (SCA3, ATXN3)
A special form of hereditary ataxia with brainstem and extrapyramidal signs has been described in patients mainly, but not exclusively, of Portuguese-Azorean origin. The disorder is characterized by an autosomal dominant pattern of inheritance and by a slowly progressive ataxia beginning in adolescence or early adult life in association with one or more features of dysarthria, hyperreflexia, extrapyramidal rigidity, dystonia, and as the illness evolves, bulbar signs, distal motor weakness, polyneuropathy, or ophthalmoplegia. There is usually no impairment of intellect and in the examples the authors have seen, the extrapyramidal symptoms were mainly rigidity and slowness of movement. Early Machado-Joseph disease characteristically demonstrates the finding of dysmetric horizontal and vertical saccades, even before the ataxia is obvious (Hotson et al).Postmortem examination discloses a degeneration of the dentate nuclei and spinocerebellar tracts and a loss of anterior horn cells and neurons of the pons, substantia nigra, and oculomotor nuclei.Cancel and colleagues found an unstable number of CAG repeating sequences in ataxin-3, and named the disorder spinocerebellar ataxia type 3 (SCA3). |
Although they can become irritated or necrotic, their removal is generally cosmetic.Dermatofibromas.Acrochordons, also known as skin tags, are benign, pedunculated lesions on the skin made up of epider-mal keratinocytes surrounding a collagenous core.They carry no malignant potential and treatment is primarily for cosmetic purposes.Soft Tissue TumorsAcrochordons.Treatment for these cystic structures includes surgical excision with care taken to remove the cyst lining to prevent recurrence.7Brunicardi_Ch16_p0511-p0540.indd 52719/02/19 3:09 PM 528SPECIFIC CONSIDERATIONSPART IIKeratosisActinic Keratosis. Actinic keratoses are neoplasms of epi-dermal keratinocytes that represent a range in a spectrum of disease from sun damage to squamous cell carcinoma. They typically occur in fair-skinned, elderly individuals in primarily sun-exposed areas, and UV radiation exposure is the greatest risk factor. There are multiple variants, and they can present as erythematous and scaly to hypertrophic, keratinized lesions. They can become symptomatic, causing bleeding, pruritis and pain. They can regress spontaneously, persist without change, and transform into invasive squamous cell carcinoma. It is estimated that approximately 10% of actinic keratoses will transform into invasive squamous cell carcinoma, and that pro-gression takes about 2 years on average.108 About 60% to 65% of squamous cell carcinomas are believed to originate from actinic keratoses. The presence of actinic keratoses also serves as a predictor of development of other squamous cell and basal cell carcinomas.109 Treatment options are excision, fluorouracil, cautery and destruction, and dermabrasion.110,111Seborrheic Keratosis. Seborrheic keratoses are benign lesions of the epidermis that typically present as well-demarcated, “stuck on” appearing papules or plaques over elderly individu-als. Clonal expansion of keratinocytes and melanocytes make up the substance of these lesions. They carry no malignant potential and treatment is primarily for cosmetic purposes.Soft Tissue TumorsAcrochordons. Acrochordons, also known as skin tags, are benign, pedunculated lesions on the skin made up of epider-mal keratinocytes surrounding a collagenous core. Although they can become irritated or necrotic, their removal is generally cosmetic.Dermatofibromas.They appear as pink to brown papules that pucker or dimple in the center when the lesion is pinched.It remains unclear whether these lesions have a neoplastic etiology or if they are the result of minor trauma or infection.112 These lesions are typically asymptomatic, and treatment is only indicated for cosmetic concerns or when a histologic diagnosis is required. |
A well-studied example of regulated polyadenylation is the switch from the synthesis of membrane-bound to secreted antibody molecules that occurs during the development of B lymphocytes (see Figure 24–22).It seems unnecessarily complex, however, to consider most of the protein variants produced by alternative RNA splicing as being derived from overlapping genes. A more sensible alternative is to modify the original definition to count a DNA sequence that is transcribed as a single unit and encodes one set of closely related polypeptide chains (protein isoforms) as a single protein-coding gene. This definition also accommodates those DNA sequences that encode protein variants produced by post-transcriptional processes other than RNA splicing, such as transcript cleavage and RNA editing (discussed below). A Change in the Site of rnA transcript Cleavage and poly-A Addition Can Change the C-terminus of a protein
We saw in Chapter 6 that the 3ʹ end of a eukaryotic mRNA molecule is not formed by the termination of RNA synthesis by the RNA polymerase, as it is in bacteria. Instead, it results from an RNA cleavage reaction that is catalyzed by additional proteins while the transcript is elongating (see Figure 6–34). A cell can control the site of this cleavage so as to change the C-terminus of the resultant protein. In the simplest cases, one protein variant is simply a truncated version of the other; in many other cases, however, the alternative cleavage and polyadenylation sites lie within intron sequences and the pattern of splicing is thereby altered. This process can produce two closely related proteins differing only in the amino acid sequences at their C-terminal ends. Close analysis of RNAs produced from the human genome in a variety of cell types (see Figure 7–3) indicate that as many as 50% of human protein-coding genes produce mRNA species that differ at their site of polyadenylation. A well-studied example of regulated polyadenylation is the switch from the synthesis of membrane-bound to secreted antibody molecules that occurs during the development of B lymphocytes (see Figure 24–22).Antigen stimulation causes B lymphocytes to multiply and to begin secreting their antibody.The secreted form of the antibody is identical to the membrane-bound form except at the extreme C-terminus. |
In the weeks ischemic chest pain who present with deep T-wave inversions in mul-and months after infarction, these ECG changes may persist or begin tiple precordial leads (e.g., V1–V4,, I, and aVL) with or without cardiac to resolve.Patients with changes in P-wave morphology, or atrial arrhythmias.Right ers of transmural myocardial infarction, whereas subendocardial ventricular ischemia usually produces ST elevations in right-sided infarcts were thought not to produce Q waves. However, careful ECG-chest leads (Fig. 268-5). When ischemic ST elevations occur as the ear-pathology correlative studies have indicated that transmural infarcts liest sign of acute infarction, they typically are followed within a period may occur without Q waves and that subendocardial (nontransmural) ranging from hours to days by evolving T-wave inversions and often infarcts sometimes may be associated with Q waves. Therefore, infarcts by Q waves occurring in the same lead distribution. Reversible trans-are more appropriately classified as “Q-wave” or “non-Q-wave.” The mural ischemia, for example, due to coronary vasospasm (Prinzmetal’s major acute ECG changes in syndromes of ischemic heart disease variant angina and possibly the Tako-tsubo “stress” cardiomyopathy are summarized schematically in Fig. 268-14. Loss of depolarizasyndrome), may cause transient ST-segment elevations without devel-tion forces due to posterior or lateral infarction may cause reciprocal opment of Q waves, as may very early reperfusion in acute coronary increases in R-wave amplitude in leads V1 and V2 without diagnostic Q syndromes. Depending on the severity and duration of ischemia, the waves in any of the conventional leads. Atrial infarction may be asso-ST elevations may resolve completely in minutes or be followed by ciated with PR-segment deviations due to an atrial current of injury, T-wave inversions that persist for hours or even days. Patients with changes in P-wave morphology, or atrial arrhythmias. In the weeks ischemic chest pain who present with deep T-wave inversions in mul-and months after infarction, these ECG changes may persist or begin tiple precordial leads (e.g., V1–V4,, I, and aVL) with or without cardiac to resolve.In descending coronary artery system (Fig.268-12). |
The resulting disorder is characterized by varying degrees of difficulty in standing and walking; in advanced cases, there is a complete failure of locomotion, although muscular power is retained.They are aware that the trouble is in the legs and not in the head, that foot placement is awkward, and that the ability to recover quickly from a misstep is impaired.To use Ramsay Hunt’s characterization, the patient with this gait disorder is recognized by his “stamp and stick.” As mentioned, the most specific feature is that the ataxia is markedly exaggerated when the patient is deprived of visual cues, as in walking in the dark. Such patients, when asked to stand with feet together and eyes closed, show greatly increased swaying and usually, the fully expressed Romberg sign with falling off to one side. It is said that in cases of sensory ataxia, the shoes do not show wear in any one place because the entire sole strikes the ground at once. Examination usually discloses a loss of position sense in the feet and legs and usually of vibratory sense as well. The peripheral or central location of the sensory lesions can be further determined by the state of the tendon reflexes. Whatever the location of the lesion, its effect is to deprive the patient of perception of the position of his limbs and, more relevant to gait, to interfere with a large amount of afferent proprioceptive and related information that does not attain conscious perception. A sense of imbalance is usually present but these patients do not describe dizziness. They are aware that the trouble is in the legs and not in the head, that foot placement is awkward, and that the ability to recover quickly from a misstep is impaired. The resulting disorder is characterized by varying degrees of difficulty in standing and walking; in advanced cases, there is a complete failure of locomotion, although muscular power is retained.This gait pattern is caused by paralysis of the pretibial and peroneal muscles, with resultant inability to dorsiflex the foot (foot drop).The steps are regular and even, but the advancing foot hangs with the toes pointing toward the ground.In its purest form, it is the result of peroneal nerve or fifth lumbar root damage. |
The first newborn examination is an important way to detect congenital malformations or deformations (Table 58-9).Physical examination also may reveal effects of the labor and delivery resulting from asphyxia, drugs, or birth trauma.Problems in the transition from fetal to neonatal life may be detectable immediately in the delivery room or during the first day of life.Before medications are administered in the presence of electrical cardiac activity with poor pulses, it is important to determine whether there is a pneumothorax. Transillumination of the thorax, involving the use of a bright light through each side of the thorax and over the sternum, may suggest pneumothorax if one side transmits more light than the other. Breath sounds may be decreased over a pneumothorax and there may be a shift of the heart tones away from the side of a tension pneumothorax. If central nervous system depression in the infant may be due to a narcotic medication given to the mother, 0.1 mg/kg of naloxone (Narcan) can be given to the infant intravenously or endotracheally. Before this drug is administered, the ABCs should be followed carefully. Naloxone should not be given to a newborn of a mother who is suspected of being addicted to narcotics or is on methadone maintenance because the newborn may experience severe withdrawal seizures. In babies of more than 35 weeks’ gestation suffering hypoxic ischemic injury at birth, induced therapeutic hypothermia(33.0°C to 34.0°C) for 72 hours has been shown in clinical studies to be efficacious in reducing the severity of brain injury. Brain hypothermia, whether induced by whole-body or selective head cooling, provides neuroprotection against encephalopathy presumably due to hypoxic ischemia. The first physical examination of a newborn may be a general physical examination of a well infant or an examination to confirm fetal diagnoses or to determine the cause of various manifestations of neonatal diseases. Problems in the transition from fetal to neonatal life may be detectable immediately in the delivery room or during the first day of life. Physical examination also may reveal effects of the labor and delivery resulting from asphyxia, drugs, or birth trauma. The first newborn examination is an important way to detect congenital malformations or deformations (Table 58-9).Signs such as cyanosis, nasal flaring, intercostal retractions, and grunting suggest pulmonary disease.Meconium staining of the umbilical cord, nails, and skin suggest fetal distress and the possibility of aspiration pneumonia.The level of spontaneous activity, passive muscle tone, quality of the cry, and apnea are useful screening signs to evaluate the state of the nervous system. |
CSF travels from each lateral ventricle through the foramina of Monroe to the third ventricle, located between the left and right thalami.The paired lateral ventricles consist of temporal, occipital, and frontal horns, as well as the main body.These structures are involved in the selection, activation and termination of movement, and facilitate learning of appropriate context-dependent motor behaviors.Lying deep to the cerebral hemispheres is the diencepha-lon, which includes the thalamus and hypothalamus. The thala-mus is a key processor and relay circuit for most motor and sensory information traveling to or from cortex. The hypothala-mus regulates homeostasis via the autonomic and neuroendo-crine systems.The brain stem consists of the midbrain (mesencephalon), pons (metencephalon), and medulla (myelencephalon). Longi-tudinal fibers run through the brain stem, carrying motor and sensory information between the cerebral hemispheres and spi-nal cord. The corticospinal tract is the major motor tract, while the medial lemniscus and spinothalamic tracts are the major sensory tracts. The nuclei of cranial nerves III through XII are also located within the brain stem. These nerves relay the motor, sensory, and special sense functions of the eye, face, mouth, and throat.The cerebellum arises from the dorsal aspect of the brain stem. It integrates somatosensory, vestibular, and motor infor-mation for coordination and timing of movement. Midline, or vermian, lesions lead to truncal ataxia. Lateral, or hemispheric, lesions lead to tremor and dyscoordination in the extremities.The ventricular system is the cerebrospinal fluid (CSF)–containing contiguous space inside the brain, continuous with the subarachnoid space outside the brain. The paired lateral ventricles consist of temporal, occipital, and frontal horns, as well as the main body. CSF travels from each lateral ventricle through the foramina of Monroe to the third ventricle, located between the left and right thalami.The foramen of Magendie (midline) and paired foram-ina of Luschka (lateral) drain to the subarachnoid space.The approximate CSF volume in an average adult is 150 mL, and the choroid plexus produces approximately 500 mL of CSF per day.The spinal cord starts at the bottom of the medulla and extends caudally through the spinal canal to the first lumbar ver-tebra, approximately. |
They also carry a high negative charge; this quality suggests that proteoglycans play a role in regulating the passage of ions across the basal lamina.Because of their highly anionic character, these molecules are extensively hydrated.This small, rodlike sulfated glycoprotein (150 kilodaltons) serves as a link between laminin and the type IV collagen network in almost all basal laminae. Each entactin molecule is organized into distinct domains that bind calcium, support cell adhesion, promote neu
FIGURE 5.29 • Electron micrograph of epithelial cells preserved by low-temperature, high-pressure freezing. This electron micrograph shows basal domain of an epithelial cell obtained from human skin. The specimen was prepared by low-temperature, high-pressure freezing, which retains more tissue components than does chemical fixation. Note that a separate lamina densa or lamina lucida is not seen in this preparation. The lamina lucida is most likely an artifact that appears as the epithelial cell shrinks away from a high concentration of macromolecules just basal of the epithelial cell. This region of highly concentrated macromolecules precipitates into the artifact known as the lamina densa. BL, basal lamina; HD, hemidesmosome; CF, collagen fibrils. 55,000. (Courtesy of Douglas R. Keene.) trophil chemotaxis and phagocytosis, and interact with laminin, perlecan, fibronectin, and type IV collagen. Proteoglycans. Most of the volume of the basal lamina is probably attributable to its proteoglycan content. Proteoglycans consist of a protein core to which heparan sulfate (e.g., perlecan, agrin), chondroitin sulfate (e.g., bamacan), or dermatan sulfate side chains are attached. Because of their highly anionic character, these molecules are extensively hydrated. They also carry a high negative charge; this quality suggests that proteoglycans play a role in regulating the passage of ions across the basal lamina.It provides additional cross-links to the basal lamina by binding to laminin, type IV collagen, and entactin/nidogen.Agrin (500 kilodaltons) is another important molecule found almost exclusively in the glomerular basement membrane of the kidney.It plays a major role in renal filtration as well as in cell-to–extracellular matrix interactions. |
Although the serum half-life averages 1 hour, the intracellular half-life of the phosphorylated compound is 3–4 hours, allowing twice-daily dosing.Zidovudine (azidothymidine; AZT) is a deoxythymidine analog that is well absorbed (63%) and distributed to most body tissues and fluids, including the cerebrospinal fluid, where drug levels are 60–65% of those in serum.Due to its activity against HBV, exacerbation of HBV may occur if therapy is interrupted or discontinued in patients co-infected with HIV and HBV. Tenofovir alafenamide is a phosphonoamidate prodrug of tenofovir that is currently available in co-formulation with other antiretroviral agents (with emtricitabine, with elvitegravir plus cobicistat plus emtricitabine, and with rilpivirine plus emtricitabine). Plasma levels of active tenofovir in plasma are approximately 90% lower with tenofovir alafenamide than with tenofovir disoproxil, since metabolism occurs in lymphocytes and macrophages (as well as hepatocytes and some other cells) rather than blood. Tenofovir alafenamide is a substrate of P-glycoprotein, and levels of tenofovir can be affected by inhibitors or inducers of P-glycoprotein. Ritonavir and cobicistat can increase plasma concentrations of tenofovir, while darunavir can decrease tenofovir concentrations. Tenofovir alafenamide appears to have less renal and bone toxicity than tenofovir disoproxil fumarate; however this is still under investigation. It does not require dose adjustment in patients with creatinine clearance >30 mL/min. Tenofovir alafenamide is a substrate of P-glycoprotein, and levels of tenofovir can be affected by inhibitors or inducers of P-glycoprotein. Ritonavir and cobicistat can increase plasma concentrations of tenofovir, while darunavir can decrease tenofovir concentrations. Adverse effects appear to be uncommon but may include gastrointestinal symptoms or headache. Tenofovir alafenamide is active against hepatitis B and has been approved for treatment of HBV infection. Zidovudine (azidothymidine; AZT) is a deoxythymidine analog that is well absorbed (63%) and distributed to most body tissues and fluids, including the cerebrospinal fluid, where drug levels are 60–65% of those in serum. Although the serum half-life averages 1 hour, the intracellular half-life of the phosphorylated compound is 3–4 hours, allowing twice-daily dosing.Zidovudine was the first antiretroviral agent to be approved and has been well studied.Studies evaluating the use of zidovudine during pregnancy, labor, and postpartum showed significant reductions in the rate of vertical transmission, and zidovudine remains one of the NRTI agents recommended for use in pregnant women (Table 49–5). |
Three NOS isozymes, each the product of a different gene, have been identified.Flavin mononucleotide (FMN), FAD, heme, and tetrahydrobiopterin (see p. 268) are coenzymes, and NO and citrulline are products of the reaction.13.9).Nitric oxide synthase Arginine, O2, and NADPH are substrates for cytosolic NO synthase ([NOS], Fig.1.In the presence of MPO, a heme-containing lysosomal enzyme present within the phagolysosome, peroxide plus chloride ions are converted to hypochlorous acid ([HOCl] the major component of household bleach), which kills the bacteria. The peroxide can also be partially reduced to the hydroxyl radical (OH•), a
ROS, or be fully reduced to H2O by catalase or glutathione peroxidase. [Note: Deficiencies in MPO do not confer increased susceptibility to infection because peroxide from NADPH oxidase is bactericidal.] G; NADP(H) = nicotinamide adenine dinucleotide phosphate; = superoxide; H2O2 = hydrogen peroxide; HOCl = hypochlorous acid; OH• = hydroxyl radical. E. Nitric oxide synthesis
Nitric oxide (NO) is recognized as a mediator in a broad array of biologic systems. NO is the endothelium-derived relaxing factor that causes vasodilation by relaxing vascular smooth muscle. It also acts as a neurotransmitter, prevents platelet aggregation, and plays an essential role in macrophage function. It has a very short half-life in tissues (3–10 seconds) because it reacts with O2 and and is converted into nitrates and nitrites including peroxynitrite (O=NOO−), a reactive nitrogen species (RNS). [Note: NO is a free radical gas that is often confused with nitrous oxide (N2O), the “laughing gas” that is used as an anesthetic and is chemically stable.] 1. Nitric oxide synthase Arginine, O2, and NADPH are substrates for cytosolic NO synthase ([NOS], Fig. 13.9). Flavin mononucleotide (FMN), FAD, heme, and tetrahydrobiopterin (see p. 268) are coenzymes, and NO and citrulline are products of the reaction. Three NOS isozymes, each the product of a different gene, have been identified.They are found primarily in endothelium (eNOS) and neural tissue (nNOS) and constantly produce very low levels of NO for vasodilation and neurotransmission.An inducible, Ca2+-independent enzyme (iNOS) can be expressed in many cells, including macrophages and neutrophils, as an early defense against pathogens. |
See text for detailed one other cell.of cases and deaths (in thousands)
FIGuRE 226-17 Typical course of an untreated HIV-infected individual.0 10 20 304050607080 Rate/100,000 population
Human Immunodeficiency Virus Disease: AIDS and Related Disorders
No.(From CDC.)The hallmark of HIV disease is a profound immunodeficiency resulting primarily from a progressive quantitative and qualitative deficiency of the subset of T lymphocytes referred to as helper T cells occurring in a setting of polyclonal immune activation. The helper subset of T cells is defined phenotypically by the presence on its surface of the CD4 molecule (Chap. 372e), which serves as the primary cellular receptor for HIV. A co-receptor must also be present together with CD4 for efficient binding, fusion, and entry of HIV-1 into its target cells (Figs. 226-3 and 226-4). HIV uses two major co-receptors, CCR5 and CXCR4, for fusion and entry; these co-receptors are also the primary receptors for certain chemoattractive cytokines termed chemo- kines and belong to the seven-transmembrane-domain G protein–coupled family of receptors. A number of mechanisms responsible for cellular depletion and/or B immune dysfunction of CD4+ T cells have been demonstrated in vitro; these include direct infection and FIGuRE 226-15 Race/ethnicity of persons (including children) diagnosed destruction of these cells by HIV, as well as indirect with HIV infection (regardless of stage) during 2011 in the United States. effects such as immune clearance of infected cells, cell
A. Estimated proportion of new infections by race/ethnicity. B. Estimated rate death associated with aberrant immune activation, and of new infections by race/ethnicity (per 100,000 population). (From CDC.) immune exhaustion due to aberrant cellular activation
FIGuRE 226-16 Estimated number of AIDS cases and AIDS deaths, United States, 1985–2011. (From CDC.) 0 10 20 304050607080 Rate/100,000 population
Human Immunodeficiency Virus Disease: AIDS and Related Disorders
No. of cases and deaths (in thousands)
FIGuRE 226-17 Typical course of an untreated HIV-infected individual. See text for detailed one other cell.For a108 variable period of time ranging from a few to several days, the virus cannot yet be detected in the plasma.This period is referred to as the “eclipse” phase of infection. |
This gene functions as a cyclic AMP–regulated chloride channel.Several other groups of investigators have documented mutations of CFTR.Since the initial discovery of the PRSS1 mutation defect, other genetic diseases have been detected (Table 371-5).It is hypothesized that this continual activation of digestive enzymes within the gland leads to acute injury and, finally, chronic pancreatitis.It is believed that alcohol or additional stimuli lead to matrix metalloproteinase–mediated destruction of normal collagen in pancreatic parenchyma, which later allows for pancreatic remodeling. Proinflammatory cytokines, tumor necrosis factor α (TNF-α), interleukin 1 (IL-1), and interleukin 6 (IL-6), as well as oxidant complexes, are able to induce PSC activity with subsequent new collagen synthesis. In addition to being stimulated by cytokines, oxidants, or growth factors, PSCs also possess transforming growth factor β (TGF-β)–mediated self-activating autocrine pathways that may explain disease progression in chronic pancreatitis even after removal of noxious stimuli. Among adults in the United States, alcoholism is the most common cause of clinically apparent chronic pancreatitis, whereas cystic fibrosis is the most frequent cause in children. As many as 25% of adults in the United States with chronic pancreatitis have the idiopathic form. Recent investigations have indicated that up to 15% of patients with idiopathic pancreatitis may have pancreatitis due to genetic defects (Table 371-5). Whitcomb and associates studied several large families with hereditary chronic pancreatitis and were able to identify a genetic defect that affects the gene encoding for trypsinogen. Several additional defects of this gene have also been described. The defect prevents the destruction of prematurely activated trypsin and allows it to be resistant to the intracellular protective effect of trypsin inhibitor. It is hypothesized that this continual activation of digestive enzymes within the gland leads to acute injury and, finally, chronic pancreatitis. Since the initial discovery of the PRSS1 mutation defect, other genetic diseases have been detected (Table 371-5). Several other groups of investigators have documented mutations of CFTR. This gene functions as a cyclic AMP–regulated chloride channel.It must be appreciated, however, that there is a great deal of heterogeneity in relationship to the CFTR gene defect.More than 1000 putative mutations of the CFTR gene have been identified.Attempts to elucidate the relationship between the genotype and pancreatic manifestations have been hampered by the number of mutations. |
6.To screen for unsuspected cancer before cosmetic operations or biopsy of a mass.5.To search for occult breast cancer in a patient with metastatic disease in axillary nodes or elsewhere from an unknown primary origin.4.To establish a baseline breast mammogram and reevaluate patients at yearly intervals to diagnose a potentially curable breast cancer before it has been diagnosed clinically.3.Results suggested that while the overall accuracy of digital and film mammography for screening breast cancer is similar, digital mammography may be more accurate in women under the age of 50 years, women with radiographically dense breast, and premenopausal or perimenopausal women (18). Slow-growing breast cancers can be identified by mammography at least 2 years before the mass reaches a size detectable by palpation. These tumors have a less aggressive biologic behavior than interval breast cancers (19–21). Mammography is the only reproducible method of detecting nonpalpable breast cancer, but its use depends on the availability of state-of-the-art equipment and a dedicated breast radiologist. Compression of the breast is necessary to obtain good images, and patients should be forewarned that breast compression is uncomfortable. With good technique and well-maintained modern equipment, exposure to radiation can be limited. Full-field digital mammography (FFDM) has a 22% lower mean glandular radiation dose than film-screen mammography per acquired view. FFDM delivers 1.86 mGy average breast radiation dose per view compared to 2.37 mGy for film screen (22). The indications for mammography are as follows: 1. To screen, at regular intervals, women who are at high risk for developing breast cancer. About one-third of the abnormalities detected on screening mammography prove malignant when biopsy is performed (23). 2. To evaluate a questionable or ill-defined breast mass or other suspicious change in the breast that is detected by clinical breast examination. 3. To establish a baseline breast mammogram and reevaluate patients at yearly intervals to diagnose a potentially curable breast cancer before it has been diagnosed clinically. 4. To search for occult breast cancer in a patient with metastatic disease in axillary nodes or elsewhere from an unknown primary origin. 5. To screen for unsuspected cancer before cosmetic operations or biopsy of a mass. 6.Screening programs to evaluate asymptomatic, healthy women combine physical examination with mammographic screening to identify breast abnormalities.During the past 30 years, there was an increase in the use of mammography, mammographic screening, and public awareness of breast health care.The cancer detection rate for screening mammography is 5 per 1,000 screening examinations (24). |
Cancer cells are found to contain mutations that drive the cell into an abnormal state, where metabolic processes may be unbalanced and essential cell components may be produced in ill-matched proportions.To survive, cancer cells require additional mutations to elude or break through these defenses against cellular misbehavior.Most normal cells stop proliferating once they have carpeted the dish with a single layer of cells: proliferation seems to depend on contact with the dish, and to be inhibited by contacts with other cells—a phenomenon known as “contact inhibition.” Cancer cells, in contrast, usually disregard these restraints and continue to grow, so that they pile up on top of one another, as shown (Movie 20.2). (A) Schematic drawing. (B and C) Light micrographs of normal (B) and transformed (C) fibroblasts. (B and C, courtesy of Lan Bo Chen.) NET PRODUCTS: NET PRODUCTS:
ENERGY, CO2, H2O ENERGY, BUILDING BLOCKS, NADPH effect—so named because Otto Warburg first noticed the phenomenon in the early twentieth century. It is this abnormally high glucose uptake that allows tumors to be selectively imaged in whole-body scans (see Figure 20–1), thereby providing a way to monitor cancer progression and responses to treatment. Cancer Cells have an Abnormal Ability to Survive Stress and DNA Damage
In a large multicellular organism, there are powerful safety mechanisms that guard against the trouble that can be caused by damaged and deranged cells. For example, internal disorder gives rise to danger signals in the faulty cell, activating protective devices that can eventually lead to apoptosis (see Chapter 18). To survive, cancer cells require additional mutations to elude or break through these defenses against cellular misbehavior. Cancer cells are found to contain mutations that drive the cell into an abnormal state, where metabolic processes may be unbalanced and essential cell components may be produced in ill-matched proportions.As one example, chromosome breakage and other forms of DNA damage are commonly observed during the development of cancer, reflecting the genetic instability that cancer cells display. |
51e-6).Rheumatic fever is the most common cause of MS (Fig.51e-1G and 51e-1H) Mid-diastolic murmurs result from obstruction and/or augmented flow at the level of the mitral or tricuspid valve.Mid-Diastolic Murmurs (Figs.270e).As the left atrial pressure becomes greater, the interval between A2 (or P2) and the opening snap (O.S.) shortens. In severe mitral stenosis, secondary pulmonary hypertension develops and results in a loud P2 and the splitting interval usually narrows. ECG, electrocardiogram. (From JA Shaver, JJ Leonard, DF Leon: Examination of the Heart, Part IV, Auscultation of the Heart. Dallas, American Heart Association, 1990, p 55. Copyright, American Heart Association.) lift and a loud, single or narrowly split S2, are present. These features also help distinguish PR from AR as the cause of a decrescendo diastolic murmur heard along the left sternal border. PR in the absence of pulmonary hypertension can occur with endocarditis or a congenitally deformed valve. It is usually present after repair of tetralogy of Fallot in childhood. When pulmonary hypertension is not present, the diastolic murmur is softer and lower pitched than the classic Graham Steell murmur, and the severity of the PR can be difficult to appreciate. TTE is indicated for the further evaluation of a patient with an early to mid-diastolic murmur. Longitudinal assessment of the severity of the valve lesion and ventricular size and systolic function help guide a potential decision for surgical management. TTE also can provide anatomic information regarding the root and proximal ascending aorta, although computed tomographic or magnetic resonance angiography may be indicated for more precise characterization (Chap. 270e). Mid-Diastolic Murmurs (Figs. 51e-1G and 51e-1H) Mid-diastolic murmurs result from obstruction and/or augmented flow at the level of the mitral or tricuspid valve. Rheumatic fever is the most common cause of MS (Fig. 51e-6).The interval between the pulmonic component of the second heart sound (P2) and the opening snap is inversely related to the magnitude of the left atrial–left ventricular pressure gradient.The murmur of MS is low-pitched and thus is best heard with the bell of the stethoscope. |
containing such gene fusions are used to infect bacteria, and the resulting phage particles have coats that express the antibody-like fusion protein, with the antigen-binding domain displayed on the outside of the bacteriophages.This technology may replace the hybridoma technology for producing monoclonal antibodies, and has the advantage that humans can be used as the source of DNA.Bacteriophages
Construct fusion protein of V region with a bacteriophage coat protein Cloning a random population of variable regions gives rise to a mixture of bacteriophages— a phage display library Select phages with desired V regions by specifc binding to antigen VH antibody protein DNA Isolate population of genes encoding antibody variable regions VH VL VL
Fig. A.10 The production of antibodies by genetic engineering. Short primers to consensus sequences in heavyand light-chain variable (V) regions of immunoglobulin genes are used to generate a library of heavyand light-chain V-region DNAs by PCR, with spleen DNA as the starting material. These heavyand light-chain V-region genes are cloned randomly into filamentous phages such that each phage expresses one heavy-chain and one light-chain V region as a surface fusion protein with antibody-like properties. The resulting phage display library is multiplied in bacteria, and the phages are then bound to a surface coated with antigen. The unbound phages are washed away; the bound phages are recovered, multiplied in bacteria, and again bound to antigen. After a few cycles, only specific high-affinity antigen-binding phages are left. These can be used like antibody molecules, or their V genes can be recovered and engineered into antibody genes to produce genetically engineered antibody molecules (not shown). This technology may replace the hybridoma technology for producing monoclonal antibodies, and has the advantage that humans can be used as the source of DNA. containing such gene fusions are used to infect bacteria, and the resulting phage particles have coats that express the antibody-like fusion protein, with the antigen-binding domain displayed on the outside of the bacteriophages.In much the same way that antibodies specific for a particular antigen can be isolated from a complex mixture by affinity chromatography (see Section A-3), phages expressing antigen-binding domains specific for a particular antigen can be isolated by selecting the phages in the library for binding to that antigen.The phage particles that bind are recovered and used to infect fresh bacteria. |
subsequent cycles, all the newly synthesized DNA molecules produced by the polymerase serve as templates for the next round of replication (Figure 8–36).The technique depends on the use of a special DNA polymerase isolated from a thermophilic bacterium; this polymerase is stable at much higher temperatures than eukaryotic DNA polymerases, so it is not denatured by the heat treatment shown in step 1. The enzyme therefore does not have to be added again after each cycle. products of frst cycle
Figure 8–36 PCR uses repeated rounds of strand separation, hybridization, and synthesis to amplify DNA. As the procedure outlined in Figure 8–35 is repeated, all the newly synthesized fragments serve as templates in their turn. Because the polymerase and the primers remain in the sample after the first cycle, PCR involves simply heating and then cooling the same sample, in the same test tube, again and again. Each cycle doubles the amount of DNA synthesized in the previous cycle, so that within a few cycles, the predominant DNA is identical to the sequence bracketed by and including the two primers in the original template. In the example illustrated here, three cycles of reaction produce 16 DNA chains, 8 of which (boxed in yellow) correspond exactly to one or the other strand of the original bracketed sequence. After four more cycles, 240 of the 256 DNA chains will correspond exactly to the original sequence, and after several more cycles, essentially all of the DNA strands will be this length. Typically, 20–30 cycles are carried out to effectively clone a region of DNA starting from genomic DNA; the rest of the genome remains unamplified, and its concentration is therefore negligible compared with that of the amplified region (Movie 8.2). subsequent cycles, all the newly synthesized DNA molecules produced by the polymerase serve as templates for the next round of replication (Figure 8–36).PCR is now the method of choice for cloning relatively short DNA fragments (say, under 10,000 nucleotide pairs).Each cycle takes only about five minutes, and automation of the whole procedure enables cell-free cloning of a DNA fragment in a few hours. |
8.288) is a branch of the maxillary artery in the infratemporal fossa.Estimating the position of the middle
The middle meningeal artery (Fig.This procedure, a tracheostomy, is a surgical procedure.Also, the presence of the isthmus of the thyroid gland and the associated vessels found in and crossing the midline makes it difficult to artificially enter the airway anteriorly through the trachea.Inferior to the cricoid cartilage, the upper cartilage of the larynx can sometimes be palpated above the level of the isthmus of the thyroid gland that crosses the trachea anteriorly. The landmarks used for finding the cricothyroid ligament are similar in men and women; however, because the laminae of the thyroid cartilage meet at a more acute angle in men, the structures are more prominent in men than in women. How to find the thyroid gland
The left and right lobes of the thyroid gland are in the anterior triangles in the lower neck on either side of the airway and digestive tract inferior to the position of the oblique line of the thyroid cartilage (Fig. 8.287). In fact, the sternothyroid muscles, which attach superiorly to the oblique lines, lie anterior to the lobes of the thyroid gland and prevent the lobes from moving upward in the neck. The lobes of the thyroid gland can be most easily palpated by finding the thyroid prominence and arch of the cricoid cartilage and then feeling posterolateral to the larynx. The isthmus of the thyroid gland crosses anterior to the upper end of the trachea and can be easily palpated in the midline inferior to the arch of the cricoid. The presence of the isthmus of the thyroid gland makes palpating the tracheal cartilages difficult in the neck. Also, the presence of the isthmus of the thyroid gland and the associated vessels found in and crossing the midline makes it difficult to artificially enter the airway anteriorly through the trachea. This procedure, a tracheostomy, is a surgical procedure. Estimating the position of the middle
The middle meningeal artery (Fig. 8.288) is a branch of the maxillary artery in the infratemporal fossa.In lateral blows to the head the middle meningeal artery can be ruptured, leading to extradural hemorrhage and eventual death if not treated.The anterior branch of the middle meningeal artery is the part of the vessel most often torn. |
Enteroviral (EV) CSF PCR appears to have a sensitivity and specificity of >95%.The sensitivity and specificity of CSF PCR tests for viruses other than HSV have not been definitively characterized.It is important to recognize that HSV CSF PCR results need to be interpreted after considering the likelihood of disease in the patient being tested, the timing of the test in relationship to onset of symptoms, and the prior use of antiviral therapy. A negative HSV CSF PCR test performed by a qualified laboratory at the appropriate time during illness in a patient with a high likelihood of HSV encephalitis based on clinical and laboratory abnormalities significantly reduces the likelihood of HSV encephalitis but does not exclude it. For example, in a patient with a pretest probability of 35% of having HSV encephalitis, a negative HSV CSF PCR reduces the posttest probability to ~2%, and for a patient with a pretest probability of 60%, a negative test reduces the posttest probability to ~6%. In both situations, a positive test makes the diagnosis almost certain (98–99%). There have been several recent reports of initially negative HSV CSF PCR tests that were obtained early (≤72 h) following symptom onset and that became positive when repeated 1–3 days later. The frequency of positive HSV CSF PCRs in patients with herpes encephalitis also decreases as a function of the duration of illness, with only ~20% of cases remaining positive after ≥14 days. PCR results are generally not affected by ≤1 week of antiviral therapy. In one study, 98% of CSF specimens remained PCR-positive during the first week of initiation of antiviral therapy, but the numbers fell to ~50% by 8–14 days and to ~21% by >15 days after initiation of antiviral therapy. The sensitivity and specificity of CSF PCR tests for viruses other than HSV have not been definitively characterized. Enteroviral (EV) CSF PCR appears to have a sensitivity and specificity of >95%.Parechoviruses are also not detected by standard EV RT-PCRs.The specificity of EBV CSF PCR has not been established.Positive EBV CSF PCRs associated with positive tests for other pathogens have been reported and may reflect reactivation of EBV latent in lymphocytes that enter the CNS as a result of an unrelated infectious or inflammatory process. |
Other causes of diarrhea—Octreotide inhibits intestinal secretion and has dose-related effects on bowel motility.2.For patients with advanced symptomatic tumors that cannot be completely removed by surgery, octreotide decreases secretory diarrhea and systemic symptoms through inhibition of hormonal secretion and may slow tumor progression.Cholestyramine and colestipol bind a number of drugs and reduce their absorption; hence, they should not be given within 2 hours of other drugs. Colesevelam does not appear to have significant effects on absorption of other drugs. Somatostatin is a 14-amino-acid peptide that is released in the gastrointestinal tract and pancreas from paracrine cells, D cells, and enteric nerves as well as from the hypothalamus (see Chapter 37). Somatostatin is a key regulatory peptide that has many physiologic effects: 1. It inhibits the secretion of numerous hormones and transmitters, including gastrin, cholecystokinin, glucagon, growth hormone, insulin, secretin, pancreatic polypeptide, vasoactive intestinal peptide, and 5-HT. 2. It reduces intestinal fluid secretion and pancreatic secretion. 3. It slows gastrointestinal motility and inhibits gallbladder contraction. 4. It reduces portal and splanchnic blood flow. 5. It inhibits secretion of some anterior pituitary hormones. The clinical usefulness of somatostatin is limited by its short half-life in the circulation (3 minutes) when it is administered by intravenous injection. Octreotide is a synthetic octapeptide with actions similar to somatostatin. When administered intravenously, it has a serum half-life of 1.5 hours. It also may be administered by subcutaneous injection, resulting in a 6to 12-hour duration of action. A longer-acting formulation is available for once-monthly depot intramuscular injection. 1. Inhibition of endocrine tumor effects—Two gastrointestinal neuroendocrine tumors (carcinoid, VIPoma) cause secretory diarrhea and systemic symptoms such as flushing and wheezing. For patients with advanced symptomatic tumors that cannot be completely removed by surgery, octreotide decreases secretory diarrhea and systemic symptoms through inhibition of hormonal secretion and may slow tumor progression. 2. Other causes of diarrhea—Octreotide inhibits intestinal secretion and has dose-related effects on bowel motility.Octreotide is effective in higher doses for the treatment of diarrhea due to vagotomy or dumping syndrome as well as for diarrhea caused by short bowel syndrome or AIDS.Octreotide has been used in low doses (50 mcg subcutaneously) to stimulate small bowel motility in patients with small bowel bacterial overgrowth or intestinal pseudo-obstruction secondary to scleroderma.3. |
Because only dividing cells can be evaluated, the rapidity with which results are obtained correlates with the rapidity of cell growth in culture.Banding of prophase chromosomes generally yields 850 bands.High-resolution metaphase banding routinely yields 450 to 550 visible bands per haploid chromosome set.he accuracy of cytogenetic analysis rises with the number of bands produced.For prenatal genetic diagnosis, the most commonly used tests are cytogenetic analysis (karyotyping), luorescence in situ hybridization (FISH), and chromosomal microarray analysis. Testing may be performed on amnionic fluid or chorionic villi. In selected circumstances, whole genome or whole exome sequencing may be considered, but these are not recommended for routine use. To diagnose a specific disease whose genetic basis is known, DNA-based tests are often employed, typically using polymerase chain reaction (PCR) for rapid ampliication of DNA sequences. Karyotype analysis is commonly performed to test for chromosomal abnormalities. Any tissue containing dividing cells or cells that can be stimulated to divide is suitable for cytogenetic analysis. Karyotyping detects numerical abnormalities, that is, aneuploidy. It also identiies balanced or unbalanced structural rearrangements of at least 5 to 10 megabases in size. Karyotyping has diagnostic accuracy exceeding 99 percent. The dividing cells are arrested in metaphase, and their chromosomes are stained to reveal light and dark bands. The most commonly used technique is Giemsa staining, which yields the G-bands shown in Figure 13-3. Each chromosome has a unique banding pattern that permits its identiication and detection of deleted, duplicated, or rearranged segments. he accuracy of cytogenetic analysis rises with the number of bands produced. High-resolution metaphase banding routinely yields 450 to 550 visible bands per haploid chromosome set. Banding of prophase chromosomes generally yields 850 bands. Because only dividing cells can be evaluated, the rapidity with which results are obtained correlates with the rapidity of cell growth in culture.Fetal blood cells may provide results in 36 to 48 hours but are rarely needed (Chap.14, p. 294).If fetal skin fibroblasts are evaluated postmortem, stimulation of cell growth can be more diicult, and cytogenetic analysis may take 2 to 3 weeks (Chap.35, p. 647). |
Piperazine The antihelminthic activity of piperazine is confined to ascariasis and enterobiasis.Pulmonary concentrations of pentamidine are increased when the drug is delivered in aerosolized form.Pentamidine does not penetrate well into the CNS.Paromomycin is less active against G. lamblia than standard agents; however, like other aminoglycosides, paromomycin is poorly absorbed from the intestinal lumen, and the high levels of drug in the gut compensate for this relatively weak activity. If absorbed or administered systemically, paromomycin can cause ototoxicity and nephrotoxicity. However, systemic absorption is very limited, and toxicity should not be a concern in persons with normal kidneys. Topical formulations are not generally available. Pentamidine Isethionate This diamidine is an effective alternative agent for some forms of leishmaniasis and trypanosomiasis. It is available for parenteral and aerosolized administration. Although its mechanism of action remains undefined, it is known to exert a wide range of effects, including interaction with trypanosomal kinetoplast DNA; interference with polyamine synthesis by a decrease in the activity of ornithine decarboxylase; and inhibition of RNA polymerase, ribosomal function, and the synthesis of nucleic acids and proteins. Pentamidine isethionate is well absorbed, is highly tissue bound, and is excreted slowly over several weeks, with an elimination half-life of 12 days. No steady-state plasma concentration is attained in persons given daily injections; the result is extensive accumulation of pentamidine in tissues, primarily the liver, kidney, adrenal, and spleen. Pentamidine does not penetrate well into the CNS. Pulmonary concentrations of pentamidine are increased when the drug is delivered in aerosolized form. Piperazine The antihelminthic activity of piperazine is confined to ascariasis and enterobiasis.Although the initial result is hyperpolarization of the muscle fibers, the ultimate effect is flaccid
CHAPTER 246e Agents Used to Treat Parasitic Infections paralysis, leading to the expulsion of live worms.Patients should be warned, as this occurrence can be unsettling. |
Given the position of the colon and rectum in the abdominopelvic cavity and its proximity to other organs, it is extremely important to accurately stage colorectal tumors: a tumor in the pelvis, for example, could invade the uterus or bladder.The anal pecten ends inferiorly at the anocutaneous line (“white line”), or where the lining of the anal canal becomes true skin.Finally, unlike the colon, the rectum lacks distinct taeniae coli muscles, omental appendices, and sacculations (haustra of the colon). The anal canal begins at the terminal end of the rectal ampulla where it narrows at the pelvic floor. It terminates as the anus after passing through the perineum. As it passes through the pelvic floor, the anal canal is surrounded along its entire length by the internal and external anal sphincters, which normally keep it closed. The lining of the anal canal bears a number of characteristic structural features that reflect the approximate position of the anococcygeal membrane in the fetus (which closes the terminal end of the developing gastrointestinal system in the fetus) and the transition from gastrointestinal mucosa to skin in the adult (Fig. 5.39B). The upper part of the anal canal is lined by mucosa similar to that lining the rectum and is distinguished by a number of longitudinally oriented folds known as anal columns, which are united inferiorly by crescentic folds termed anal valves. Superior to each valve is a depression termed an anal sinus. The anal valves together form a circle around the anal canal at a location known as the pectinate line, which marks the approximate position of the anal membrane in the fetus. Inferior to the pectinate line is a transition zone known as the anal pecten, which is lined by nonkeratinized stratified squamous epithelium. The anal pecten ends inferiorly at the anocutaneous line (“white line”), or where the lining of the anal canal becomes true skin. Given the position of the colon and rectum in the abdominopelvic cavity and its proximity to other organs, it is extremely important to accurately stage colorectal tumors: a tumor in the pelvis, for example, could invade the uterus or bladder.The pelvic parts of the urinary system consist of the terminal parts of the ureters, the bladder, and the proximal part of the urethra (Fig.5.40).The ureters enter the pelvic cavity from the abdomen by passing through the pelvic inlet.On each side, the ureter crosses the pelvic inlet and enters the pelvic cavity in the area anterior to the bifurcation of the common iliac artery. |
Knowledge of how the visual field is represented throughout the visual pathway is essential for identifying the location of lesions in patients with visual field deficits.Because of this, the optic tracts, thalamus, optic radiations, and primary visual cortex receive information relating only to the contralateral half of the visual field.As they leave the optic disc they form the optic nerve, acquire a myelin sheath provided by oligodendrocytes, and are invested by the cranial meninges (eFig. 9.72). These morphological features derived during embryonic development, define the optic nerve as a component of the CNS. Anterior to the infundibular stalk, the optic nerves converge at the optic chiasm. Within the chiasm, axons from the nasal portion of the retina decussate and enter into the contralateral optic tract (eFig. 9.75). Conversely, axons from the temporal portion of the retina stay ipsilateral to enter the ipsilateral optic tract (eFig. 9.75). Continuing posteriorly, the optic tracts course around the midbrain to enter the lateral geniculate nucleus of the thalamus (eFig. 9.75). At this level, a small portion of the fibers from the optic tract travel to the pretectal area and superior colliculus to mediate the pupillary light reflex. Axons leaving the lateral geniculate nucleus form the optic radiations, which continue on to the primary visual cortex in the occipital lobe (eFig. 9.76). Fibers traveling in the lower portion of the optic radiations terminate on the lower half of the primary visual cortex, whereas fibers in the upper portion terminate on the upper half of the cortex (eFig. 9.76). A full review of how the visual field is represented throughout the visual pathway can be reviewed in eFig. 9.77. As mentioned previously, images formed on the retina are inverted in both vertical and lateral dimensions. In addition, the fibers from the nasal portion of the hemiretina decussate at the optic chiasm. Because of this, the optic tracts, thalamus, optic radiations, and primary visual cortex receive information relating only to the contralateral half of the visual field. Knowledge of how the visual field is represented throughout the visual pathway is essential for identifying the location of lesions in patients with visual field deficits.9.78.Part IX: Auditory and
Cranial nerve VIII, the vestibulocochlear nerve, conveys sensory information from the vestibular and auditory organs of the inner ear to the pontomedullary junction of the brainstem.Although these sensory modalities are conveyed to the brainstem by a common nerve bundle, each of these sensory functions has different central pathways. |
Oocyte donors may be anonymous or known to the recipient (96).A gestational carrier receives and gestates birth embryos created from the intended mother’s oocytes. Patients who choose to utilize a gestational carrier may have irreparable uterine factor infertility or suffer from medical conditions that contraindicate pregnancy. In true surrogacy, the birth mother is the genetic mother but not the intended mother. Legal and psychosocial counseling are suggested for all parties embarking on any form of third party reproduction. Donor Oocyte Patients with ovarian failure, poor oocyte quality, poor ovarian response to stimulation, or failed fertilization or implantation after multiple ART cycles may be candidates to receive donated oocytes. A female same-sex couple may choose to have one partner undergo IVF and place the resulting oocytes fertilized with donor sperm into the other partner (383). At present, donor oocytes must be used to create embryos during the retrieval cycle, because oocyte freezing is considered experimental (384). With carefully selected donors, live birth rates per cycle of donor oocyte IVF are 50% to 60% regardless of the recipient’s age (Table 32.10). However, recipients must be aware that advanced recipient age is associated with higher risk for preeclampsia, diabetes, and cesarean section (385–387). Oocyte donors must endure all the interventions and risks of the ART process described herein except for embryo transfer and luteal support. Because of the intensity of therapy and the potential infectious disease and genetic risks for donor, recipient, and the resulting offspring, oocyte donors must be screened for infectious and heritable disorders similar to those performed for sperm donors (see “Male Factor”) and undergo meticulous informed consent and a comprehensive psychosocial evaluation. Oocyte donors may be anonymous or known to the recipient (96).Recipients may initiate progesterone one day prior, on the same day, or one day after the donor’s oocyte retrieval, but a randomized trial found lower pregnancy rates when progesterone was initiated prior to the retrieval (377).Other topics, such as methods for donor recruitment and financial compensation for the donor, are much more challenging issues (388). |
In patients with poor pulmonary reserve, the transhiatal esophagectomy should be considered, as the pulmonary morbidity of this operation is less than is seen following thoracotomy.Any patient with a forced expi-ratory volume in 1 second of <1.25 L is a poor candidate for thoracotomy because he or she has a 40% risk of dying from respiratory insufficiency within 4 years.If there is invasion into the pleura (T4a), then surgical resection can be considered in the absence of a malignant effusion. Thus, it can be seen that the therapy of esophageal cancer is largely driven by the findings of an endoscopic ultrasonography. It is difficult to provide modern treatment of esophageal cancer without access to this modality.PET scanning, usually combined with an axial CT scan (CTPET), usually is performed on patients with locally advanced cancer or questionable lesions on CT scan to deter-mine whether metastases are present. The PET scan uses the injection of radiolabeled deoxyglucose, which is taken up in metabolically active tissues such as cancer. PET-positive areas must be correlated with the CT scan findings to assess the sig-nificance of “hot spots.” CTPET scanning has been especially useful before the initiation of chemoradiation therapy. An early response to chemoradiotherapy, by PET scan, improves the prognosis whether or not resection is ultimately performed. Conversely, if a PET-avid tumor shows no change in metabolic activity after 2 weeks of induction chemoradiation therapy, it is unlikely that further chemoor radiation therapy will be of invasive surgery may reduce the morbidity and mortality associ-ated with open twoor three-field esophagectomy.Cardiopulmonary Reserve. Patients undergoing esophageal resection should have sufficient cardiopulmonary reserve to tol-erate the proposed procedure. The respiratory function is best assessed with the forced expiratory volume in 1 second, which ideally should be 2 L or more. Any patient with a forced expi-ratory volume in 1 second of <1.25 L is a poor candidate for thoracotomy because he or she has a 40% risk of dying from respiratory insufficiency within 4 years. In patients with poor pulmonary reserve, the transhiatal esophagectomy should be considered, as the pulmonary morbidity of this operation is less than is seen following thoracotomy.Echocardiography and dipyridamole thallium imaging provide accurate information on wall motion, ejection fraction, and myocardial blood flow.A defect on thallium imaging may require further evaluation with preoperative coronary angiogra-phy.A resting ejection fraction of <40%, particularly if there is no increase with exercise, is an ominous sign. |
Ethanol causes vasodilation (which increases heat loss), reduces thermogenesis and gluconeogenesis, and may impair judgment or lead to obtundation.Hunters, sailors, skiers, and climbers also are at great risk of exposure, whether it involves injury, changes in weather, or lack of preparedness.Military history is replete with hypothermic tragedies.Primary accidental hypothermia is a result of the direct exposure of a previously healthy individual to the cold. The mortality rate is much higher for patients who develop secondary hypothermia as a complication of a serious systemic disorder. Primary accidental hypothermia is geographically and seasonally pervasive. Although most cases occur in the winter months and in colder climates, this condition is surprisingly common in warmer regions as well. Multiple variables render individuals at the extremes of age— both the elderly and neonates—particularly vulnerable to hypothermia (Table 478e-1). The elderly have diminished thermal perception and are more susceptible to immobility, malnutrition, and systemic illnesses that interfere with heat generation or conservation. Dementia, psychiatric illness, and socioeconomic factors often compound these problems by impeding adequate measures to prevent hypothermia. Neonates have high rates of heat loss because of their increased surface-to-mass ratio and their lack of effective shivering and adaptive behavioral responses. At all ages, malnutrition can contribute to heat loss because of diminished subcutaneous fat and as a result of depleted energy stores used for thermogenesis. Individuals whose occupations or hobbies entail extensive exposure to cold weather are at increased risk for hypothermia. Military history is replete with hypothermic tragedies. Hunters, sailors, skiers, and climbers also are at great risk of exposure, whether it involves injury, changes in weather, or lack of preparedness. Ethanol causes vasodilation (which increases heat loss), reduces thermogenesis and gluconeogenesis, and may impair judgment or lead to obtundation.Up to 25% of patients admitted to an intensive care unit because of drug overdose are hypothermic.Anesthetics can block shivering responses; their effects are compounded when patients are not insulated adequately in the operating or recovery units.Several types of endocrine dysfunction can lead to hypothermia. |
Renal biopsy can confirm the presence of pauci-immune glomerulonephritis.Biopsy of upper airway tissue usually reveals granulomatous inflammation with necrosis but may not show vasculitis.Pulmonary tissue offers the highest diagnostic yield, almost invariably revealing granulomatous vasculitis.Fever may indicate activity of the underlying disease but more often reflects secondary infection, usually of the upper airway. Characteristic laboratory findings include a markedly elevated erythrocyte sedimentation rate (ESR), mild anemia and leukocytosis, mild hypergammaglobulinemia (particularly of the IgA class), and mildly elevated rheumatoid factor. Thrombocytosis may be seen as an acute-phase reactant. Approximately 90% of patients with active granulomatosis with polyangiitis (Wegener’s) have a positive antiproteinase-3 ANCA. However, in the absence of active disease, the sensitivity drops to ∼60–70%. A small percentage of patients with granulomatosis with polyangiitis (Wegener’s) may have antimyeloperoxidase rather than antiproteinase-3 antibodies, and up to 20% may lack ANCA. Patients with granulomatosis with polyangiitis (Wegener’s) have been found to have an increased incidence of venous thrombotic events. Although routine anticoagulation for all patients is not recommended, a heightened awareness for any clinical features suggestive of deep venous thrombosis or pulmonary emboli is warranted. The diagnosis of granulomatosis with polyangiitis (Wegener’s) is made by the demonstration of necrotizing granulomatous vasculitis on tissue biopsy in a patient with compatible clinical features. Pulmonary tissue offers the highest diagnostic yield, almost invariably revealing granulomatous vasculitis. Biopsy of upper airway tissue usually reveals granulomatous inflammation with necrosis but may not show vasculitis. Renal biopsy can confirm the presence of pauci-immune glomerulonephritis.False-positive ANCA titers have been reported in certain infectious and neoplastic diseases.In its typical presentation, the clinicopathologic complex of granulomatosis with polyangiitis (Wegener’s) usually provides ready differentiation from other disorders. |
All aspects of speech and language are affected.Almost invariably, in cases of global aphasia, there is a degree of right hemiplegia, hemianesthesia, and homonymous hemianopia.The cause is usually an occlusion of the proximal left middle cerebral artery, but it may be the result of hemorrhage, tumor, abscess or other lesions, and transiently as a postictal effect.Usually, there is no weakness of limbs or face for which reason the fluently aphasic patient may be misdiagnosed as psychotic or confused, especially if there is jargon aphasia. According to Kertesz and Benson, persistence of Wernicke aphasia is related to a lesion that involves both the left supramarginal and angular gyri and therefore, elements of Gerstmann syndrome may be evident. The posterior perisylvian region, therefore, appears to encompass a variety of language functions, and seemingly minor changes in the size and locale of the lesion are associated with important variations in the elements of Wernicke aphasia or lead to conduction aphasia, pure word blindness, or to pure word deafness (see the following text). The interesting theoretical problem is whether all the deficits observed are indicative of a unitary language function that resides in the posterior perisylvian region or, instead, of a series of separate sensorimotor activities whose anatomic pathways happen to be crowded together in a small region of the brain. In view of the multiple ways in which language is learned and deteriorates in disease, the latter hypothesis seems more likely. This syndrome is caused by destruction of a large part of the language zone, embracing both Broca and Wernicke areas and much of the territory between them. The cause is usually an occlusion of the proximal left middle cerebral artery, but it may be the result of hemorrhage, tumor, abscess or other lesions, and transiently as a postictal effect. Almost invariably, in cases of global aphasia, there is a degree of right hemiplegia, hemianesthesia, and homonymous hemianopia. All aspects of speech and language are affected.Many are initially mute.They may understand a few words and phrases, but, because of rapid fatigue and verbal and motor perseveration—they characteristically fail to carry out a series of simple commands or to name a series of objects.They cannot read or write or repeat what is said to them. |
The seizures are treated with antiepileptic drugs, which may at first be held responsible for the ataxia.In all of these conditions, the ataxia, which is of cerebellar type, is variable from time to time and may follow a burst of seizures (such as occur in argininosuccinic aciduria).Impaired intestinal transport of tryptophan and loss in the urine reduce its availability for the synthesis of niacin and accounts for the pellagrous skin changes. The pathologic basis of the disease is undetermined. It must be differentiated from the large number of intermittent and progressive cerebellar ataxias of childhood, described below. Treatment consists of avoiding exposure to sunlight and to sulfonamide drugs. Because of the similarities between pellagra and Hartnup disease, the usual practice is to give nicotinamide in doses of 50 to 300 mg daily. The skin lesions disappear and there are reports of subsidence of ataxia and psychotic behavior. However, the results of treatment are inconsistent. Possibly a better response is obtained by the administration of l-tryptophan ethyl ester in doses of 20 mg/kg tid. Other Metabolic Diseases With Episodic or Persistent Ataxia, Seizures, and Developmental Delay
In addition to Hartnup disease, a number of other metabolic diseases give rise to intermittent episodes of ataxia during early childhood. These are (1) mild forms of maple syrup urine disease and the congenital hyperammonemias (type II hyperammonemia, citrullinemia, argininosuccinic aciduria, hyperornithinemia), described in an earlier part of the chapter; (2) subacute necrotizing encephalomyelopathy (Leigh disease), described further on; (3) hyperalaninemia and hyperpyruvic acidemia (Lonsdale et al; Blass et al); and (4) autosomal dominant, acetazolamide-responsive ataxia that may have its onset in childhood but usually appears later (see Griggs et al); and (5) familial hypobetalipoproteinemia—Bassen-Kornzweig disease. In all of these conditions, the ataxia, which is of cerebellar type, is variable from time to time and may follow a burst of seizures (such as occur in argininosuccinic aciduria). The seizures are treated with antiepileptic drugs, which may at first be held responsible for the ataxia.Indeed, seizures and ataxia are both a result of the common biochemical abnormality.Between attacks, in all the intermittent ataxias, the patient’s movements are relatively normal, but most of the affected children have learning disabilities to a varying degree.Progressive Cerebellar Ataxia of Early Childhood
The differentiation among the childhood ataxias is difficult. |
(NotethattetrodotoxinandtetraethylammoniumwerepresenttoblockNa+ andK+ conductancetoisolatetheCa++ conductance.6.4 PresynapticCa++ currentanditsrelationshiptothepostsynapticresponse.A, Schematicofasquidgiantsynapsepreparation.Electrodes1and2areusedtovoltage-clampthepresynapticterminalandrecorditsvoltageandcurrent.Normally an action potential in a motor neuron causes a large depolarization in the postsynaptic muscle, termed an end plate potential (EPP), which is equivalent to an EPSP in a neuron. However, under conditions of low extracellular [Ca++], the EPP amplitude is reduced (because the presynaptic Ca++ current is reduced, leading to a smaller rise in intracellular [Ca++], and transmitter release is proportional to [Ca++]). In this condition, the EPP is seen to fluctuate among discrete values (
Fig. 6.5 ). Moreover, small spontaneous depolarizations of the postsynaptic membrane, termed miniature end plate potentials (mEPPs), are observable. The amplitude of the mEPP (≤1 mV) corresponds to that of the smallest EPP evoked under low [Ca++], and the amplitudes of other EPPs were shown to be integral multiples of the mEPP amplitude; thus, it was proposed that each mEPP corresponded
SynthesizedandpackagedinthenerveterminalSynthesizedandpackagedinthecellbody;transportedtothenerveterminalbyfastaxonaltransportSynthesizedinactiveformActivepeptideformedwhenitiscleavedfromamuchlargerpolypeptidethatcontainsseveralneuropeptidesUsuallypresentinsmallclearvesiclesUsuallypresentinlargeelectron-densevesiclesReleasedintoasynapticcleftMaybereleasedsomedistancefromthepostsynapticcellTheremaybenowell-definedsynapticstructureActionofmanyterminatedbecauseofuptakebypresynapticActionterminatedbyproteolysisorbythepeptidediffusingawayterminalsviaNa+-poweredactivetransportTypically,actionhasshortlatencyandshortduration(msec)Actionmayhavelonglatencyandmaypersistformanyseconds •Fig. 6.4 PresynapticCa++ currentanditsrelationshiptothepostsynapticresponse.A, Schematicofasquidgiantsynapsepreparation.Electrodes1and2areusedtovoltage-clampthepresynapticterminalandrecorditsvoltageandcurrent. (NotethattetrodotoxinandtetraethylammoniumwerepresenttoblockNa+ andK+ conductancetoisolatetheCa++ conductance. |
Other medications for the treatment of PMS and PMDD are shown in Table 12.2.It is thought that the mode of action of SSRIs when used in this fashion differs from that which alleviates major depression (65).The medication is packaged for this specific indication and dosage.Records of emotions and behaviors should be kept separate from menstrual records to avoid confounding patients’ perceptions. At the same time, the patient must be screened for other psychiatric disorders, including depression and personality disorders, and for domestic abuse and other life circumstances that may contribute to her psychological state (58). No treatment for PMS has been validated by empirical studies (59). Studies of St. John’s wort, possibly the most popular alternative treatment, are contradictory (60). A number of lifestyle changes and other benign interventions alleviate symptoms for some patients with PMS (61):
Elimination of caffeine from the diet
Stress reduction can be accomplished by reducing or delegating responsibilities, insofar as that is possible, and devoting part of every day to relaxation techniques such as meditation and yoga. Many women experience stress factors over which they have no control (59). For premenstrual dysphoric disorder, several selective serotonin reuptake inhibitors (SSRIs) proved effective in clinical trials (62–65). Although SSRIs and all other antidepressants require about 2 weeks of daily administration to achieve therapeutic effect for other depressive disorders, it appears that fluoxetine is effective for PMDD when taken in the usual daily doses for the 1 to 2 weeks preceding menstruation. The medication is packaged for this specific indication and dosage. It is thought that the mode of action of SSRIs when used in this fashion differs from that which alleviates major depression (65). Other medications for the treatment of PMS and PMDD are shown in Table 12.2.Symptoms must be carefully monitored to determine whether the hormonal intervention improves or exacerbates the problem mood changes.Infertility is described by most women who undergo treatment for it as the most stressful event of their lives.Each unsuccessful treatment episode is experienced as the loss of a hoped-for pregnancy (67). |
Human chorionic somatomammotropin (hCS), also known as human placental lactogen (hPL), is closely related to human growth hormone.Two other clinical conditions that increase the blood levels of hCG include trophoblastic diseases and ectopic pregnancies.Measurement of hCG is used to detect early pregnancy and assess pregnancy viability.The maternal blood finally leaves the intervillous space (black arrows) through endometrial veins. The fetal blood enters the placenta through the umbilical arteries that divide into a series of radially disposed arteries within the chorionic plate. Branches from the vessels pass into the main stem villi and there form extensive capillary networks. The veins within the villi then carry the blood back through a system of veins that parallels the fetal arteries. removed or fails to function. In the production of placental estrogen, the fetal adrenal cortex plays an essential role, providing the precursors needed for estrogen synthesis. Because the placenta lacks the enzymes needed for the production of estrogen precursors, a cooperative fetoplacental (endocrine) unit is established. Clinically, the monitoring of estrogen production during pregnancy can be used as an index of fetal development. The following peptide hormones are secreted by the placenta: Human chorionic gonadotropin (hCG) is required for implantation and maintenance of the pregnancy. Its synthesis begins around day 6, even before the syncytiotrophoblast is formed. HCG exhibits extensive (about 85%) sequence homology to LH, which is required for ovulation and maintenance of the corpus luteum during the menstrual cycle. Similar to the work of LH during the menstrual cycle, hCG maintains the corpus luteum during early pregnancy. HCG also possesses marked homology to pituitary thyroid-stimulating hormone (TSH), which may account for hyperthyroidism in pregnancy by stimulating the maternal thyroid gland to increase secretion of tetraiodothyronine (T4). Measurement of hCG is used to detect early pregnancy and assess pregnancy viability. Two other clinical conditions that increase the blood levels of hCG include trophoblastic diseases and ectopic pregnancies. Human chorionic somatomammotropin (hCS), also known as human placental lactogen (hPL), is closely related to human growth hormone.The effects of hCS on maternal metabolism are significant, but the role of this hormone in fetal development remains unknown. IGF-I and IGF-II are produced by and stimulate proliferation and differentiation of the cytotrophoblast. Endothelial growth factor (EGF) exhibits an age-dependent dual action on the early placenta. |
Leprosy frequently involves the facial nerve, and facial neuropathy may also occur in diabetes mellitus, connective tissue diseases including Sjögren’s syndrome, and amyloidosis.460).390) and in Guillain-Barré syndrome (Chap.Facial palsy that is often bilateral occurs in sarcoidosis (Chap.Herpes simplex virus (HSV) type 1 DNA was frequently detected in endoneurial fluid and posterior auricular muscle, suggesting that a reactivation of this virus in the geniculate ganglion may be responsible for most cases. Reactivation of varicella-zoster virus is associated with Bell’s palsy in up to one-third of cases and may represent the second most frequent cause. A variety of other viruses have also been implicated less commonly. An increased incidence of Bell’s palsy was also reported among recipients of inactivated intranasal influenza vaccine, and it was hypothesized that this could have resulted from the Escherichia coli enterotoxin used as adjuvant or reactivation of latent virus. Differential Diagnosis There are many other causes of acute facial palsy that must be considered in the differential diagnosis of Bell’s palsy. Lyme disease can cause unilateral or bilateral facial palsies; in endemic areas, 10% or more of cases of facial palsy are likely due to infection with Borrelia burgdorferi (Chap. 210). The Ramsay Hunt syndrome, caused by reactivation of herpes zoster in the geniculate ganglion, consists of a severe facial palsy associated with a vesicular eruption in the external auditory canal and sometimes in the pharynx and other parts of the cranial integument; often the eighth cranial nerve is affected as well. Facial palsy that is often bilateral occurs in sarcoidosis (Chap. 390) and in Guillain-Barré syndrome (Chap. 460). Leprosy frequently involves the facial nerve, and facial neuropathy may also occur in diabetes mellitus, connective tissue diseases including Sjögren’s syndrome, and amyloidosis.Its cause is unknown.Acoustic neuromas frequently involve the facial nerve by local compression.Infarcts, demyelinating lesions of MS, and tumors are the common pontine lesions that interrupt the facial nerve fibers; other signs of brainstem involvement are usually present. |
Fatigue and exertional dyspnea owing to reduced forward CO are early symptoms of isolated, severe TR.Because TR most often coexists with left-sided valve lesions, LV dysfunction, and/or PA hypertension, symptoms related to these lesions may dominate the clinical picture.Mild or moderate degrees of TR are usually well tolerated in the absence of other hemodynamic disturbances.Less commonly, TR results from congenitally deformed tricuspid valves, and it occurs with defects of the atrioventricular canal, as well as with Ebstein’s malformation of the tricuspid valve (Chap. 282). The incompetent tricuspid valve allows blood to flow backward from the RV into the RA, the volume of which is dependent on the driving pressure (i.e., RV systolic pressure) and the size of the regurgitant orifice. The severity and physical signs of TR can vary as a function of PA systolic pressure (in the absence of RV outflow tract stenosis), the dimension of the tricuspid valve annulus, the respiratory cycle– dependent changes in RV preload, and RA compliance. RV filling is increased during inspiration. Forward CO is reduced and does not augment with exercise. Significant degrees of TR will lead to RA enlargement and elevation of the RA and jugular venous pressures with prominent c-v waves in the pulse tracings. Progressively severe TR can lead to “ventricularization” of the RA wave form (see Fig. 267-1B). Severe TR is also characterized by RV dilation (RV volume overload) and eventual systolic dysfunction, the rate of which can be accelerated by a concomitant pressure load from PA hypertension or by myocardial fibrosis from previous injury. Mild or moderate degrees of TR are usually well tolerated in the absence of other hemodynamic disturbances. Because TR most often coexists with left-sided valve lesions, LV dysfunction, and/or PA hypertension, symptoms related to these lesions may dominate the clinical picture. Fatigue and exertional dyspnea owing to reduced forward CO are early symptoms of isolated, severe TR.The neck veins in patients with severe TR are distended with prominent c-v waves and rapid y descents (in the absence of TS).TR is more often diagnosed by examination of the neck veins than by auscultation of the heart sounds.Other findings may include marked hepatomegaly with systolic pulsations, ascites, pleural effusions, edema, and a positive hepatojugular reflex. |
Surgery is usually the most effective method of managing otosclero-sis; more than 90% of patients experience complete elim-ination of conductive hearing loss.It is FOLDER 25.1 Clinical Correlation: Otosclerosis
Otosclerosis is one of most common causes of acquired hearing loss. It is reported that about 13% of the U.S. population has nonclinical otosclerosis (histologic oto-sclerosis); however, incidence of clinical disease ranges from 0.5% to 1.0%. Individuals with otosclerosis complain about progressive hearing loss. Symptoms usually become apparent between ages 20 and 45. Otosclerosis is a metabolic bone disease that uniquely affects the temporal bone and ossicles and is characterized by abnormal bone remodeling. The stimulus to initiate bone remodeling in oto-sclerosis is still unknown, but recent studies associate this event with measles virus infection. Mature bone in the area of the oval window on the medial wall of the tympanic cav-ity, which separates the middle ear from the internal ear, is removed by osteoclasts and replaced with much thicker immature (woven) bone. Since the footplate of the stapes normally resides and freely vibrates within the oval window to allow the transmission of sound into the internal ear, the bone remodeling in this area results in fixation of the stapes into the surrounding bone. The cemented (or frozen in place) stapes does not vibrate and prevents sound waves from reaching the perilymphatic fluid space of the internal ear, causing conductive hearing loss. The treatment of otosclerosis includes several options: phar-macologic treatment to suppress bone remodeling with fluorides and bisphosphonates, amplification of sounds with hearing aids, and surgical removal of the stapes (stapedectomy) with subsequent implantation of a pros-thesis between the incus and the oval window. Surgery is usually the most effective method of managing otosclero-sis; more than 90% of patients experience complete elim-ination of conductive hearing loss.Auditory disorders are classified as either sen-sorineural or conductive.Conductive hearing loss results when sound waves are mechanically impeded from reaching the auditory sensory receptors within the internal ear.This type of hearing loss principally involves the external ear or structures of the middle ear. |
B: Estrogen ligand binds to membrane-bound ER and activates the mitogenactivated protein kinase (MAPK) pathways that support ER-mediated transcription.The ER is subsequently phosphorylated, undergoes dimerization, and binds to the estrogen response element (ERE) on the promoter of an estrogen responsive gene.A: 17β-estrodiol diffuses through the cell membrane and binds to cytoplasmic ER.Mutations of hormone receptors may also contribute to the progression of neoplastic disease and resistance to hormone therapy (32,33). Growth Factors Growth factors are polypeptides that are produced by a variety of cell types and exhibit a wide range of overlapping biochemical actions. Growth factors bind to high-affinity cell membrane receptors and trigger complex positive and negative signaling pathways that regulate cell proliferation and differentiation (34). In general, growth factors exert positive or negative effects upon the cell cycle by influencing gene expression related to events that occur at the G1-S cell cycle boundary (35). Because of their short half-life in the extracellular space, growth factors act over limited distances through autocrine or paracrine mechanisms. In the autocrine loop, the growth factor acts on the cell that produced it. The paracrine mechanism of growth control involves the effect of growth factors on another cell in proximity. Growth factors that play an important role in female reproductive physiology are listed in Table 6.3. The biologic response of a cell
ERE 5’ GGTCAnnnTGACC 3’ MAPKER A B C PKA IGF EGF c-myc, c-fos, c-jun,IGF, BCL-2 β
Figure 6.4 Activation of estrogen receptor mediated transcription. Intracellular estrogen receptor signaling is mediated via different pathways. A: 17β-estrodiol diffuses through the cell membrane and binds to cytoplasmic ER. The ER is subsequently phosphorylated, undergoes dimerization, and binds to the estrogen response element (ERE) on the promoter of an estrogen responsive gene. B: Estrogen ligand binds to membrane-bound ER and activates the mitogenactivated protein kinase (MAPK) pathways that support ER-mediated transcription.to a specific growth factor depends on a variety of factors, including the cell type, the cellular microenvironment, and the cell cycle status.The regulation of ovarian function occurs through autocrine, paracrine, and endocrine mechanisms (36–42).The growth and differentiation of ovarian cells are particularly influenced by the insulinlike growth factors (IGF) (Fig.6.5). |
In children with signs of head or neck trauma, the jaw thrust maneuver should be used.The head tilt–chin lift maneuver should be used to open the airway in children with no sign of head or neck trauma.Ventilation is extremely important in pediatric arrests because of the high likelihood of a primary respiratory cause; however, ventilation requires
Brain Seizures, cerebral edema, infarction, herniation, anoxic damage, SIADH, diabetes insipidus
Cardiovascular Heart failure, myocardial infarct
Lung and pulmonary Acute respiratory distress syndrome, vasculature pulmonary hypertension Liver Infarction, necrosis, cholestasis Kidney Acute tubular necrosis, acute cortical
Gastrointestinal Gastric ulceration, mucosal damage tract Hematologic Disseminated intravascular coagulation
SIADH, Syndrome of inappropriate secretion of antidiuretic hormone. equipment and is, therefore, sometimes delayed. For this reason the recommendation is to start chest compressions first while preparing for ventilation. For optimal chest compressions, the child should be supine on a flat, hard surface. Effective CPR requires a compression depth of one third to one half of the anterior-posterior diameter of the chest with complete recoil after each compression. The compression rate should be at least 100/min with breaths delivered 8 to 10 times per minute. If an advanced airway is in place, compressions should not pause for ventilation; both should continue simultaneously. Ventilation requires a patent airway. In children, airway patency often is compromised by a loss of muscle tone, allowing the mandibular block of tissue, including the tongue, bony mandible, and the soft surrounding tissues, to rest against the posterior pharyngeal wall. The head tilt–chin lift maneuver should be used to open the airway in children with no sign of head or neck trauma. In children with signs of head or neck trauma, the jaw thrust maneuver should be used.If skilled personnel and proper equipment are available, pediatric patients requiring resuscitation should be endotracheally intubated.Before intubation, the patient should be ventilated with 100% oxygen using a bag and mask.Cricoid pressure should be used to minimize inflation of the stomach. |
However, most if not all polypeptides and proteins have specific carrier proteins (e.g., insulin growth factor–binding protein (IGFBP).In addition, some cells express receptors for hormones that they secrete. This type of hormonal action is referred to as autocrine control. These hormones regulate the cell’s own activity. Figure 21.1 summarizes various hormonal control mechanisms. Hormones include three classes of compounds. Cells of the endocrine system release more than 100 hormones and hormonally active substances that are chemically divided into three classes of compounds: Steroids, cholesterol-derived compounds, are synthesized and secreted by cells of the ovaries, testes, and adrenal cortex. These hormones (gonadal and adrenocortical steroids) are released into the bloodstream and transported to target cells with the help of plasma proteins or specialized carrier proteins such as androgen-binding protein. Hormone-binding carrier proteins protect the hormone from degradation during transport to the target tissue. When needed, the hormone is released from the carrier protein to become active. Small peptides, polypeptides,and proteins are synthesized and secreted by cells of the hypothalamus, pituitary gland, thyroid gland, parathyroid gland, pancreas, and scattered enteroendocrine cells of the gastrointestinal tract and respiratory system. This group of hormones (e.g., insulin, glucagon, growth hormone [GH], adreno corticotropic hormone [ACTH], follicle-stimulating hormone [FSH], luteinizing hormone [LH], antidiuretic hormone [ADH], oxytocin, interleukins, and various growth factors), when released into the circulation, dissolve readily in the blood and generally do not require special transport proteins. However, most if not all polypeptides and proteins have specific carrier proteins (e.g., insulin growth factor–binding protein (IGFBP).They are synthesized and secreted by many neurons as well as a variety of cells including cells of the adrenal medulla.Also included in this group of compounds are thyroid hormones, the iodinated derivatives of the amino acid tyrosine that are synthesized and secreted by the thyroid gland. |
Mobitz type II is presentwhen the PR interval does not change, but a QRS is intermittently dropped.It is oftenseen during sleep, usually does not progress to other forms ofheart block, and does not require further evaluation or treatment in otherwise normal children.The premature beat is not preceded by a P wave and the QRS complex is wide and bizarre. If the heart is structurally normal, and the PVCs are singleton, uniform in focus, and disappear with increased heart rate. The PVCs are usually benign and require no treatment. Any deviation from the presentation (history of syncope or a family history of sudden death) requires further investigation and possibly treatment with antiarrhythmic medications. Ventricular tachycardia, defined as three or more consecutive PVCs, is also relatively rare in pediatric patients. Although there are multiple causes of ventricular tachycardia, it usually is a sign of serious cardiac dysfunction or disease. Rapid-rate ventricular tachycardia results in decreased cardiac output and cardiovascular instability. Treatment in symptomatic patients is synchronized cardioversion. Medical management with lidocaine or amiodarone may be appropriate in a conscious asymptomatic patient. Complete evaluation of the etiologic picture is necessary, including electrophysiologic study. Firstdegree heart block is the presence of a prolonged PRinterval. It is asymptomatic and, when present in otherwisenormal children, requires no evaluation or treatment. Seconddegree heart block is when some, but not all, of the P waves are followed by a QRS complex. Mobitz type I (also known asWenckebach) is characterized by a progressive prolongationof the PR interval until a QRS complex is dropped. It is oftenseen during sleep, usually does not progress to other forms ofheart block, and does not require further evaluation or treatment in otherwise normal children. Mobitz type II is presentwhen the PR interval does not change, but a QRS is intermittently dropped.Thirddegree heart block, whether congenital or acquired, is present when thereis no relationship between atrial and ventricular activity.Theventricular rate is much slower than the atrial rate.Congenital complete heart block is associated with maternal collagen vascular disease (such as systemic lupus erythematosus or Sjögrensyndrome) or congenital heart disease. |
Bilateral high-voltage slow waves in the range of 2 to 4 per second (delta) or 5 to 7 per second (theta) are the usual findings with confusion.2, the electroencephalogram (EEG) is almost invariably abnormal in even mild forms of this syndrome, in contrast to delirium tremens, where the changes may be relatively minor.As discussed in Chap.Concussion and seizures, especially petit mal or temporal lobe status epilepticus or the postictal state, and certain focal (e.g., right parietal and temporal) cerebral lesions may also be followed by a period of confusion. Focal lesions, most often infarctions but also hemorrhages, of the right cerebral hemisphere may evoke an acute confusional state. Such syndromes have been described with strokes mainly in the territory of the right middle cerebral artery (Mesulam et al; Caplan et al; Mori and Yamadori); usually the infarcts have involved the posterior parietal lobe or inferior frontostriatal regions, but they have also occurred with strokes in the territory of one posterior cerebral artery. A variety of more generalized or multifocal cerebral diseases may be associated with transient or persistent confusional states. Among these are meningitis, encephalitis, thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation, tumors, subdural hematoma, and cranial trauma. A more restricted group of focal cerebral diseases, including drug and alcohol withdrawal and systemic infections cause delirium, as discussed below. Pathophysiology of Confusional States
All that has been said on this subject in Chap. 16 regarding coma is applicable to at least one subgroup of the confusional states. In most cases, no consistent pathologic change is found because the abnormalities are metabolic and subcellular. As discussed in Chap. 2, the electroencephalogram (EEG) is almost invariably abnormal in even mild forms of this syndrome, in contrast to delirium tremens, where the changes may be relatively minor. Bilateral high-voltage slow waves in the range of 2 to 4 per second (delta) or 5 to 7 per second (theta) are the usual findings with confusion.If only theoretically, mental incoherence and the disorganized thinking and behavior of the confusional states reflect the loss of integrated activity of all of the associative regions of the cortex as mentioned earlier in the chapter.This is best depicted in the patient undergoing withdrawal from alcohol after a sustained period of intoxication, that is, delirium tremens. |
Impairment of the renal function may coexist, although the occurrence of renal insufficiency prior to the development of hypertension is uncommon.Other less common causes of renal artery stenosis include renal artery aneurysm (compressing the adjacent normal renal artery), arteriovenous malformations, neurofibromatosis, renal artery dissections, renal artery trauma, Takayasu’s arteritis, and renal arteriovenous fistula.Clinical ManifestationsRenovascular hypertension is the most common sequela of renal artery occlusive disease. Its prevalence varies from 2% in patients with diastolic blood pressure greater than 100 mmHg to almost 30% in those with diastolic blood pressure over 125 mmHg.103 Clinical features that may indicate the presence of renovascular hypertension include the following: (a) systolic and diastolic upper abdominal bruits; (b) diastolic hypertension of greater than 115 mmHg; (c) rapid onset of hypertension after the age of 50 years; (d) a sudden worsening of mild to moder-ate essential hypertension; (e) hypertension that is difficult to control with three or more antihypertensives; (f) development of renal insufficiency after angiotensin-converting enzyme inhibi-tors; and (g) development of hypertension during childhood.103All patients with significant hypertension, especially ele-vated diastolic blood pressure, must be considered as suspect for renovascular disease. Young adults with hypertension have a great deal to gain by avoiding lifelong treatment if renovascular hypertension is diagnosed and corrected. Appropriate diagnostic studies and intervention must be timely instituted to detect the possibility of renovascular hypertension in patients with pri-mary hypertension who present for clinical evaluation.Diagnostic EvaluationThe diagnostic requisites for renovascular hypertension include both hypertension and renal artery stenosis. Impairment of the renal function may coexist, although the occurrence of renal insufficiency prior to the development of hypertension is uncommon.The follow-ing section provides an overview of the strengths and limitations of the most common tests used in the diagnostic evaluation of the patient with suspected renovascular hypertension prior to intervention.Captopril renal scanning is a functional study that assesses renal perfusion before and after administration of the angioten-sin-converting enzyme inhibitor captopril. |
Vitamin E deficiency may also occur as a consequence of various cholestatic and hepatobiliary disorders as well as short-bowel syndromes resulting from the surgical treatment of intestinal disorders.There are genetic forms of isolated vitamin E deficiency not associated with lipid malabsorption.Patients with cystic fibrosis may also have vitamin E deficiency secondary to steatorrhea.With progression, patients develop features of a nonspecific generalized polyneuropathy, with distal sensory loss in the feet and hands. Blood and urine assays for thiamine are not reliable for diagnosis of deficiency. Erythrocyte transketolase activity and the percentage increase in activity (in vitro) following the addition of thiamine pyrophosphate (TPP) may be more accurate and reliable. EDx shows nonspecific findings of an axonal sensorimotor polyneuropathy. When a diagnosis of thiamine deficiency is made or suspected, thiamine replacement should be provided until proper nutrition is restored. Thiamine is usually given intravenously or intramuscularly at a dose of 100 mg/d. Although cardiac manifestations show a striking response to thiamine replacement, neurologic improvement is usually more variable and less dramatic. The term vitamin E is usually used for a-tocopherol, the most active of the four main types of vitamin E. Because vitamin E is present in animal fat, vegetable oils, and various grains, deficiency is usually due to factors other than insufficient intake. Vitamin E deficiency usually occurs secondary to lipid malabsorption or in uncommon disorders of vitamin E transport. One hereditary disorder is abetalipoproteinemia, a rare autosomal dominant disorder characterized by steatorrhea, pigmentary retinopathy, acanthocytosis, and progressive ataxia. Patients with cystic fibrosis may also have vitamin E deficiency secondary to steatorrhea. There are genetic forms of isolated vitamin E deficiency not associated with lipid malabsorption. Vitamin E deficiency may also occur as a consequence of various cholestatic and hepatobiliary disorders as well as short-bowel syndromes resulting from the surgical treatment of intestinal disorders.The onset of symptoms tends to be insidious, and progression is slow.The main clinical features are spinocerebellar ataxia and polyneuropathy, thus resembling Friedreich’s ataxia or other spinocerebellar ataxias.Patients manifest progressive ataxia and signs of posterior column dysfunction, such as impaired joint position and vibratory sensation. |
Sleep-related hypoventilation can be distin- features and findings on polysomnography.Other breathing-related sleep disorders.Sleep—related hypoventila- tion must be distinguished from other causes of sleep-related hypoxemia, such as that due to lung disease.However, obtaining arterial blood gas determinations dur- ing sleep is impractical, and non-invasive measures of pC02 have not been adequately val- idated during sleep and are not widely used during polysomnography in adults. Prolonged and sustained decreases in oxygen saturation (oxygen saturation of less than 90% for more than 5 minutes with a nadir of at least 85%, or oxygen saturation of less than 90% for at least 30% of sleep time) in the absence of evidence of upper airway obstruction are often used as an indication of sleep-related hypoventilation; however, this finding is not specific, as there are other potential causes of hypoxemia, such as that due to lung disease. The consequences of sleep-related hypoventilation are related to the effects of chronic ex- posure to hypercapnia and hypoxemia. These blood gas derangements cause vasocon- striction of the pulmonary vasculature leading to pulmonary hypertension, which, if severe, can result in right-sided heart failure (cor pulmonale). Hypoxemia can lead to dys- function of organs such as the brain, blood, and heart, leading to outcomes such as cog- nitive dysfunction, polycythemia, and cardiac arrhythmias. Hypercapnia can depress ventilatory drive, leading to progressive respiratory failure. Other medical conditions affecting ventilation. In adults, the idiopathic variety of sleep- related hypoventilation is very uncommon and is determined by excluding the presence of lung diseases, skeletal malformations, neuromuscular disorders, and other medical and neurological disorders or medications that affect ventilation. Sleep—related hypoventila- tion must be distinguished from other causes of sleep-related hypoxemia, such as that due to lung disease. Other breathing-related sleep disorders. Sleep-related hypoventilation can be distin- features and findings on polysomnography.Obstructive sleep apnea hy- popnea and central sleep apnea also show a pattern of discrete episodes of repeated air- flow decreases that can be absent in sleep-related hypoventilation. |
Its principal disadvantage is a risk of blood dyscrasias.The model “atypical” antipsy chotic agent is clozapine, a dibenzodiazepine that has a greater potency in blocking the 5-HT2 than the D2 receptor and a much higher affinity for the D4 than the D2 receptor.Schizophrenia-prone families are also at risk for other psychiatric disorders, including schizoaffective disorder and schizotypal and schizoid personality disorders, the latter terms designating individuals who show a lifetime pattern of social and interpersonal deficits characterized by an inability to form close interpersonal relationships, eccentric behavior, and mild perceptual distortions. Antipsychotic agents (Table 466-10) are the cornerstone of acute and maintenance treatment of schizophrenia and are effective in the treatment of hallucinations, delusions, and thought disorders, regardless of etiology. The mechanism of action involves, at least in part, binding to dopamine D2/D3 receptors in the ventral striatum; the clinical potencies of traditional antipsychotic drugs parallel their affinities for the D2 receptor, and even the newer “atypical” agents exert some degree of D2 receptor blockade. All neuroleptics induce expression of the immediate-early gene c-fos in the nucleus accumbens, a dopaminergic site connecting prefrontal and limbic cortices. The clinical efficacy of newer atypical neuroleptics, however, may involve N-methyl-D-aspartate (NMDA) receptor blockade, α1-and α2-2721 noradrenergic activity, altering the relationship between 5-HT2 and D2 receptor activity, and faster dissociation of D2 binding and effects on neuroplasticity. Conventional neuroleptics differ in their potency and side effect profile. Older agents, such as chlorpromazine and thioridazine, are more sedating and anticholinergic and more likely to cause orthostatic hypotension, whereas higher potency antipsychotics, such as haloperidol, perphenazine, and thiothixene, are more likely to induce extrapyramidal side effects. The model “atypical” antipsy chotic agent is clozapine, a dibenzodiazepine that has a greater potency in blocking the 5-HT2 than the D2 receptor and a much higher affinity for the D4 than the D2 receptor. Its principal disadvantage is a risk of blood dyscrasias.Unlike other antipsychotics, clozapine does not cause a rise in prolactin level.Approximately 30% of patients who do not benefit from conventional antipsychotic agents will have a better response to this drug, which also has a demonstrated superiority to other antipsychotic agents in preventing suicide; however, its side effect profile makes it most appropriate for treatment-resistant cases. |
From an evolution-ary perspective, given that eukaryotic mitochondria derive from bacterial origin, it would make sense that they retain bacterial features capable of eliciting a strong response that is typically associated with a pathogen trigger. In addition, the mitochon-drial transcription factor A (TFAM), a highly abundant mito-chondrial protein, is functionally and structurally homologous to HMGB1. It has also been shown be released in high amounts from damaged cells where it acts in conjunction with mtDNA to activate TLR9 signaling.20Following trauma, cf-mtDNA levels appear to be higher in nonsurvivors when compared to survivors and correlate with the development of both SIRS and sepsis post injury.21,22 Cf-mtDNA has also been linked both ex vivo and in vivo to the formation of neutrophil extracellular traps, which are also associated with sterile inflammation and are a possible cause of secondary tissue injury.23,24 Reducing cf-mtDNA, perhaps by targeting enzymes capable of digesting circulating mtDNA is an attractive therapeutic option to prevent development of inflam-matory complications of trauma.25Heat-Shock Proteins as DAMPs. Heat shock proteins (HSPs) are a large and diverse family of intracellular proteins that are expressed during times of inflammation and oxidative stress or following tissue injury.26 Very highly conserved across species, HSPs function as molecular chaperones to monitor and maintain appropriate protein folding.27 They accomplish this task through the promotion of protein refolding, the targeting of misfolded proteins for degradation, or the sequestering of partially folded proteins for movement to appropriate membrane compartments.For example, HSP70-containing exosomes have been implicated in postshock inflammation.29 Once outside the cell, free HSPs can bind to pattern-recognition receptors (PRR) as well as other cell surface receptors to modu-late the inflammatory response. |
ECGs can be useful in detecting old myocardial infarction, dilation or hypertrophy of the cardiac chambers, arrhythmias, and conduction abnormali-ties.Electrocardiograms (ECGs) and chest X-rays are noninvasive diagnostic studies that provide invaluable information in the preoperative assess-ment of patients with cardiac pathology.The previous guidelines included inter-mediate and low cardiovascular risk profiles, but this has been replaced by cardiovascular risk factors in the update. These risk factors are: history of ischemic heart disease, history of prior or compensated heart failure, history of cerebrovascular dis-ease, diabetes mellitus, and renal insufficiency. Based on the number of present risk factors and the surgery-specific risk, the guidelines recommend pathways for further evaluation and risk management. The most recent guidelines from ACC/AHA were published in 2014 (Fig. 21-1).7 One important subgroup of patients at elevated risk are those who have recently undergone percutaneous coronary intervention. In these patients, elective noncardiac surgery should be delayed until the risk of stent thrombosis decreases (30 days for bare metal stents and 180 to 365 days for drug-eluting stents), and dual antiplatelet therapy should be continued unless the risk of bleeding exceeds the risk of stent thrombosis.5Diagnostic StudiesElectrocardiogram and Chest X-ray. Electrocardiograms (ECGs) and chest X-rays are noninvasive diagnostic studies that provide invaluable information in the preoperative assess-ment of patients with cardiac pathology. ECGs can be useful in detecting old myocardial infarction, dilation or hypertrophy of the cardiac chambers, arrhythmias, and conduction abnormali-ties.Echocardiography utilizes reflected sound waves to image the heart.Transthoracic echocardiography (TTE) is used widely due to its noninvasive nature.It is the pri-mary diagnostic tool used to evaluate structural diseases of the heart, including valvular pathology, septal defects, cardiomyop-athies, and cardiac masses. |
Mild diarrhea and abdominal pain are uncommon side effects of these agents.These medications are contraindicated in pregnancy, however.once) is effective.Albendazole (400 mg once), mebendazole (100 g twice daily for 3 days or 500 mg once), or ivermectin (150–200 μg/kg aTime from infection to egg production by mature female worm.Single worms may cause disease when they migrate into aberrant sites. A large worm can enter and occlude the biliary tree, causing biliary colic, cholecystitis, cholangitis, pancreatitis, or (rarely) intrahepatic abscesses. Migration of an adult worm up the esophagus can provoke coughing and oral expulsion of the worm. In highly endemic areas, intestinal and biliary ascariasis can rival acute appendicitis and gallstones as causes of surgical acute abdomen. Laboratory Findings Most cases of ascariasis can be diagnosed by microscopic detection of characteristic Ascaris eggs (65 by 45 μm) in fecal samples. Occasionally, patients present after passing an adult worm— identifiable by its large size and smooth cream-colored surface—in the stool or, much less commonly, through the mouth or nose. During the early transpulmonary migratory phase, when eosinophilic pneumonitis occurs, larvae can be found in sputum or gastric aspirates before diagnostic eggs appear in the stool. The eosinophilia that is prominent during this early stage usually decreases to minimal levels in established infection. Adult worms may be visualized, occasionally serendipitously, on contrast studies of the gastrointestinal tract. A plain abdominal film may reveal masses of worms in gas-filled loops of bowel in patients with intestinal obstruction. Pancreaticobiliary worms can be detected by ultrasound and endoscopic retrograde cholangiopancreatography; the latter method also has been used to extract biliary Ascaris worms. Ascariasis should always be treated to prevent potentially serious complications. Albendazole (400 mg once), mebendazole (100 g twice daily for 3 days or 500 mg once), or ivermectin (150–200 μg/kg aTime from infection to egg production by mature female worm. once) is effective. These medications are contraindicated in pregnancy, however. Mild diarrhea and abdominal pain are uncommon side effects of these agents.Two hookworm species (A. duodenale and N. americanus) are responsible for human infections.Most infected individuals are asymptomatic.Hookworm disease develops from a combination of factors—a heavy worm burden, a prolonged duration of infection, and an inadequate iron intake—and results in iron-deficiency anemia and, on occasion, hypoproteinemia. |
Pretreatment staging of rectal carcinoma often relies on endorectal ultrasound or MRI to determine the T and N status of a rectal cancer.29-26).These operations are best performed in tertiary centers with multidisciplinary teams consisting of a colon and rectal surgeon, urologist, neurosurgeon, and plastic surgeon.Stage-Specific Therapy (Fig.ca = carcinoma.Brunicardi_Ch29_p1259-p1330.indd 129923/02/19 2:29 PM 1300SPECIFIC CONSIDERATIONSPART IIstill attempt to obtain a 2-cm distal mural margin for curative resections.Total mesorectal excision (TME) is a technique that uses sharp dissection along anatomic planes to ensure complete resection of the rectal mesentery during low and extended low anterior resections. For upper rectal or rectosigmoid resections, a partial mesorectal excision of at least 5 cm distal to the tumor appears adequate. TME both decreases local recurrence rates and improves long-term survival rates. Moreover, this tech-nique is associated with less blood loss and less risk to the pel-vic nerves and presacral plexus than is blunt dissection. The principles of TME should be applied to all radical resections for rectal cancer.Recurrence of rectal cancer generally has a poor prog-nosis. Extensive involvement of other pelvic organs (usually occurring in the setting of tumor recurrence) may require a pelvic exenteration. The rectal and perineal portions of this operation are similar to an APR, but en bloc resection of the ureters, bladder, and prostate or uterus and vagina are also per-formed. A permanent colostomy and an ileal conduit to drain the urinary tract may be necessary. The sacrum may also be resected if necessary (sacrectomy) up to the level of the S2-S3 junction. These operations are best performed in tertiary centers with multidisciplinary teams consisting of a colon and rectal surgeon, urologist, neurosurgeon, and plastic surgeon.Stage-Specific Therapy (Fig. 29-26). Pretreatment staging of rectal carcinoma often relies on endorectal ultrasound or MRI to determine the T and N status of a rectal cancer.Ultrasound evaluation can guide choice of therapy in most patients.MRI is useful to assess mesorectal involvement.When the radial margin is threatened or involved, neoadjuvant chemoradiation is recommended.122Stage 0 (Tis, N0, M0) Villous adenomas harboring carci-noma in situ (high-grade dysplasia) are ideally treated with local excision.A 1-cm margin should be obtained. |
These zoonotic organisms include Streptococcus equi subspecies zooepidemicus and S. equi subspecies equi.Distinct streptococcal species of Lancefield group C cause infections in domesticated animals, especially horses and cattle; some human infections are acquired through contact with animals or consumption of unpasteurized milk.Asymptomatic pharyngeal colonization with GAS has been detected in up to 25% of persons with >4 h/d of same-room exposure to an index case. However, antibiotic prophylaxis is not routinely recommended for contacts of patients with invasive disease because such an approach (if effective) would require treatment of hundreds of contacts to prevent a single case. Group C and group G streptococci are β-hemolytic bacteria that occasionally cause human infections similar to those caused by GAS. Strains that form small colonies on blood agar (<0.5 mm) are generally members of the Streptococcus milleri (Streptococcus intermedius, Streptococcus anginosus) group (see “Viridans Streptococci,” below). 969 Large-colony group C and G streptococci of human origin are now considered a single species, Streptococcus dysgalactiae subspecies equisimilis. These organisms have been associated with pharyngitis, cellulitis and soft tissue infections, pneumonia, bacteremia, endocarditis, and septic arthritis. Puerperal sepsis, meningitis, epidural abscess, intraabdominal abscess, urinary tract infection, and neonatal sepsis have also been reported. Group C or G streptococcal bacteremia most often affects elderly or chronically ill patients and, in the absence of obvious local infection, is likely to reflect endocarditis. Septic arthritis, sometimes involving multiple joints, may complicate endocarditis or develop in its absence. Distinct streptococcal species of Lancefield group C cause infections in domesticated animals, especially horses and cattle; some human infections are acquired through contact with animals or consumption of unpasteurized milk. These zoonotic organisms include Streptococcus equi subspecies zooepidemicus and S. equi subspecies equi.Antibiotic treatment is the same as for similar syndromes due to GAS (Table 173-3).Patients with bacteremia or septic arthritis should receive IV penicillin (2–4 mU every 4 h).All group C and G streptococci are sensitive to penicillin; nearly all are inhibited in vitro by concentrations of ≤0.03 μg/mL. |
An inferior fibular retinaculum attaches to the lateral surface of the calcaneus around the fibular trochlea and blends above with the fibers of the inferior extensor retinaculum.6.112):
A superior fibular retinaculum extends between the lateral malleolus and the calcaneus.The pulse of the posterior tibial artery can be felt through the flexor retinaculum midway between the medial malleolus and the calcaneus. Lateral to the tibial nerve is the compartment on the posterior surface of the talus and the undersurface of the sustentaculum tali for the tendon of the flexor hallucis longus muscle. Two extensor retinacula strap the tendons of the extensor muscles to the ankle region and prevent tendon bowing during extension of the foot and toes (Fig. 6.111):
A superior extensor retinaculum is a thickening of deep fascia in the distal leg just superior to the ankle joint and attached to the anterior borders of the fibula and tibia. An inferior retinaculum is Y-shaped, attached by its base to the lateral side of the upper surface of the calcaneus, and crosses medially over the foot to attach by one of its arms to the medial malleolus, whereas the other arm wraps medially around the foot and attaches to the medial side of the plantar aponeurosis. The tendons of the extensor digitorum longus and fibularis tertius pass through a compartment on the lateral side of the proximal foot. Medial to these tendons, the dorsalis pedis artery (terminal branch of the anterior tibial artery), the tendon of the extensor hallucis longus muscle, and finally the tendon of the tibialis anterior muscle pass under the extensor retinacula. Fibular (peroneal) retinacula bind the tendons of the fibularis longus and fibularis brevis muscles to the lateral side of the foot (Fig. 6.112):
A superior fibular retinaculum extends between the lateral malleolus and the calcaneus. An inferior fibular retinaculum attaches to the lateral surface of the calcaneus around the fibular trochlea and blends above with the fibers of the inferior extensor retinaculum.Arches of the foot
The bones of the foot do not lie in a horizontal plane.Instead, they form longitudinal and transverse arches relative to the ground (Fig.6.113), which absorb and distribute downward forces from the body during standing and moving on different surfaces.The longitudinal arch of the foot is formed between the posterior end of the calcaneus and the heads of the metatarsals (Fig. |
When conditions for viral growth are optimal, a virus-encoded protein called Tat, which binds to a specific stem-loop structure in the nascent RNA that contains a “bulged base,” prevents this premature termination (see Figure 6–89).in addition, rnA splicing, rnA editing, and translation recoding can also alter the sequence of amino acids in a protein, making it possible for the cell to produce more than one protein variant from the same gene. Only a few of the steps depicted here are likely to be critical for the regulation of any one particular protein. transcription Attenuation Causes the premature termination of Some rnA Molecules
It has long been known that the expression of some genes is inhibited by premature termination of transcription, a phenomenon called transcription attenuation. In some of these cases, the nascent RNA chain adopts a structure that causes it to interact with the RNA polymerase in such a way as to abort its transcription. When the gene product is required, regulatory proteins bind to the nascent RNA chain and remove the attenuation, allowing the transcription of a complete RNA molecule. A well-studied example of transcription attenuation occurs during the life cycle of HIV, the human immunodeficiency virus that is the causative agent of acquired immune deficiency syndrome, or AIDS. Once the HIV genome has been integrated into the host genome, the viral DNA is transcribed by the cell’s RNA polymerase II (see Figure 5–62). However, this polymerase usually terminates transcription after synthesizing transcripts of several hundred nucleotides and therefore fails to efficiently transcribe the entire viral genome. When conditions for viral growth are optimal, a virus-encoded protein called Tat, which binds to a specific stem-loop structure in the nascent RNA that contains a “bulged base,” prevents this premature termination (see Figure 6–89).The normal role of at least some of these proteins is to prevent pausing and premature termination by RNA polymerase when it transcribes normal cell genes.Thus, a normal cell mechanism has apparently been highjacked by HIV to permit transcription of its genome to be controlled by a single viral protein. |
The usual dose is 25 mg orally daily.Alogliptin lowers HbA1c by about 0.5–0.6% when added to metformin, sulfonylurea, or pioglitazone.The risk of pancreatitis may be increased.Adverse reactions include nasopharyngitis and hypersensitivity reactions (urticaria, angioedema, localized skin exfoliation, bronchial hyperreactivity).The major metabolite is active, and excretion is by both renal and hepatic pathways. The terminal plasma half-life is 2.5 hours for saxagliptin and 3.1 hours for its active metabolite. Dosage adjustment is recommended for individuals with renal impairment and concurrent use of strong CYP3A4/5 inhibitors such as antiviral, antifungal, and certain antibacterial agents. It is approved as monotherapy and in combination with biguanides, sulfonylureas, and thiazolidinediones. During clinical trials, monoand combination therapy with saxagliptin resulted in an HbA1c reduction of 0.4–0.9%. Adverse effects include an increased rate of infections (upper respiratory tract and urinary tract), headaches, and hypersensitivity reactions (urticaria, facial edema). The dosage of a concurrently administered insulin secretagogue or insulin may need to be lowered to prevent hypoglycemia. Saxagliptin may increase the risk of heart failure. In a postmarketing study of 16,492 type 2 diabetes patients, there were 289 cases of heart failure in the saxagliptin group (3.5%) and 228 cases in the placebo group (2.8%)—a hazard ratio of 1.27. Patients at the highest risk for failure were those who had a history of heart failure or had elevated levels of N-terminal of the prohormone brain natriuretic peptide (NTpBNP) or had renal impairment. Linagliptin lowers HbA1c by 0.4–0.6% when added to metformin, sulfonylurea, or pioglitazone. The dosage is 5 mg daily orally and, since it is primarily excreted via the bile, no dosage adjustment is needed in renal failure. Adverse reactions include nasopharyngitis and hypersensitivity reactions (urticaria, angioedema, localized skin exfoliation, bronchial hyperreactivity). The risk of pancreatitis may be increased. Alogliptin lowers HbA1c by about 0.5–0.6% when added to metformin, sulfonylurea, or pioglitazone. The usual dose is 25 mg orally daily.In clinical trials, pancreatitis occurred in 11 of 5902 patients on alogliptin (0.2%) and in 5 of 5183 patients receiving all comparators (<0.1%).There have been reports of hypersensitivity reactions (anaphylaxis, angioedema, Stevens-Johnson syndrome).Cases of hepatic failure have been reported, but it is unclear if alogliptin was the cause. |
The involved skin is initially tender, erythematous, and warm.Temperature abnormalities, both hyperthermia and hypothermia, are concomitant with the release of bacterial toxins and with bacterial sepsis (104).Late in the course of the infection, the involved skin may be anesthetized secondary to necrosis of superficial nerves.Systemic toxicity is a frequent feature of this disease, as manifested by the presence of dehydration, septic shock, disseminated intravascular coagulation, and multiple organ system failure. The pathogenesis of necrotizing fasciitis involves a polymicrobial infection of the dermis and subcutaneous tissue. Hemolytic streptococcus was initially believed to be the primary pathogen responsible for the infection in necrotizing fasciitis (103). Other organisms are often cultured in addition to streptococcus, including other gram-positive organisms, coliforms, and anaerobes (104). Bacterial enzymes such as hyaluronidase and lipase released in the subcutaneous space destroy the fascia and adipose tissue and induce a liquefactive necrosis. Noninflammatory intravascular coagulation or thrombosis subsequently occurs. Intravascular coagulation results in ischemia and necrosis of the subcutaneous tissues and skin. Subcutaneous spread of up to 1 inch per hour can be seen, often with little effect on the overlying skin (104). Late in the course of the infection, destruction of the superficial nerves produces anesthesia in the involved skin. The release of bacteria and bacterial toxins into the systemic circulation can cause septic shock, acid-base disturbances, and multiple organ impairment. The diagnosis is often difficult to make early in the disease course. Most patients with necrotizing fasciitis develop erythema, edema, and pain, which in the early stages of the disease is disproportionately greater than that expected from the degree of cellulitis present and characteristically extends beyond the border of erythema (105). Late in the course of the infection, the involved skin may be anesthetized secondary to necrosis of superficial nerves. Temperature abnormalities, both hyperthermia and hypothermia, are concomitant with the release of bacterial toxins and with bacterial sepsis (104). The involved skin is initially tender, erythematous, and warm.Subcutaneous microvascular thrombosis induces ischemia in the skin, which becomes cyanotic and blistered.As necrosis develops, the skin becomes gangrenous and may slough spontaneously (104).Most patients will have leukocytosis and acid-base abnormalities.Subcutaneous gas may develop, which can be identified by palpation and by radiography. |
Similarly, no protective effect was found in a large study that examined whether giving low-dose parenteral insulin could delay the onset of diabetes in people at high risk of developing the disease.As discussed in Section 14-13, this principle has been applied with some success to the treatment of allergies caused by an IgE response to very low doses of antigen. Repeated treatment of allergic individuals with increasing doses of allergen seems to divert the allergic response to one dominated by T cells that favor the production of IgG and IgA antibodies from B cells. These antibodies are thought to desensitize the patient by binding the small amounts of allergen normally encountered and preventing it from binding to IgE. There has been considerable interest in using peptide antigens to suppress pathogenic responses in T-cell-mediated autoimmune disease. The type of CD4 T-cell response induced by a peptide depends on the way in which it is presented to the immune system (see Section 9-18). For instance, peptides given orally tend to induce regulatory T cells through production of transforming growth factor (TGF)-β, but do not induce TH1 cells or systemic antibody production (see Section 12-14). Indeed, experiments in animals indicate that oral antigens can protect against induced autoimmune disease. Diseases resembling multiple sclerosis or rheumatoid arthritis can be induced in mice by the injection of myelin basic protein (MBP) or collagen type II, respectively, in Freund’s complete adjuvant (see Section 16-29). Oral administration of MBP or type II collagen inhibits the development of these diseases in animals, but oral administration of the whole protein in patients with multiple sclerosis or rheumatoid arthritis has had marginal therapeutic effects. Similarly, no protective effect was found in a large study that examined whether giving low-dose parenteral insulin could delay the onset of diabetes in people at high risk of developing the disease.The peptide drug glatiramer acetate (Copaxone) is approved for treating multiple sclerosis, in which it may reduce relapse rates by up to 30%.It is a polymer consisting of the four amino acids glutamic acid, alanine, tyrosine, and lysine in ratios that mimic their composition in MBP, and it induces a TH2-type protective response. |
The resulting diseases are best considered in terms of the functional defects of adherence, chemotaxis, and microbicidal activity.Abnormal Neutrophil Function Inherited and acquired abnormalities of phagocyte function are listed in Table 80-3.In a leukemoid reaction, the circulating neutrophils are usually mature and not clonally derived.Cause of Indicated Dysfunction
Adherence-aggregation Aspirin, colchicine, alcohol, glucocorti-Neonatal state, hemodialysis Leukocyte adhesion deficiency types 1, 2, coids, ibuprofen, piroxicam and 3
Deformability Leukemia, neonatal state, diabetes mellitus, immature neutrophils
Chemokinesis-chemotaxis Glucocorticoids (high dose), auranofin, Thermal injury, malignancy, malnutrition, Chédiak-Higashi syndrome, neutrophilcolchicine (weak effect), phenylbu-periodontal disease, neonatal state, systemic specific granule deficiency, hyper IgE–recurtazone, naproxen, indomethacin, lupus erythematosus, rheumatoid arthritis, rent infection (Job’s) syndrome (in some interleukin 2 diabetes mellitus, sepsis, influenza virus patients), Down’s syndrome, α-mannosidase infection, herpes simplex virus infection, deficiency, leukocyte adhesion deficiencies, acrodermatitis enteropathica, AIDS Wiskott-Aldrich syndrome
Microbicidal activity Colchicine, cyclophosphamide, gluco-Leukemia, aplastic anemia, certain neutrope-Chédiak-Higashi syndrome, neutrophil-specorticoids (high dose), TNF-α-blocking nias, tuftsin deficiency, thermal injury, sepsis, cific granule deficiency, chronic granulomaantibodies neonatal state, diabetes mellitus, malnutri-tous disease, defects in IFNγ/IL-12 axis tion, AIDS
Abbreviations: IFNγ, interferon γ; IL, interleukin; TNF-α, tumor necrosis factor alpha. often used to distinguish this degree of neutrophilia from leukemia. In a leukemoid reaction, the circulating neutrophils are usually mature and not clonally derived. Abnormal Neutrophil Function Inherited and acquired abnormalities of phagocyte function are listed in Table 80-3. The resulting diseases are best considered in terms of the functional defects of adherence, chemotaxis, and microbicidal activity.All are autosomal recessive and result in the inability of neutrophils to exit the circulation to sites of infection, leading to leukocytosis and increased susceptibility to infection (Fig.80-8).Patients with LAD 1 have mutations in CD18, the common component of the integrins LFA-1, Mac-1, and p150,95, leading to a defect in tight adhesion between neutrophils and the endothelium. |
(B) The structure of the β2-adrenergic receptor, a receptor for the neurotransmitter adrenaline, illustrates the typical cylindrical arrangement of the seven transmembrane helices in a GPCR.GPCRs that bind protein ligands have a large extracellular domain (not shown here) that contributes to ligand binding.When a GPCR is activated, it acts like a guanine nucleotide exchange factor (GEF) and induces the α subunit to release its bound GDP, allowing GTP to bind in its place. GTP binding then causes an activating conformational change in the Gα subunit, releasing the G protein from the receptor and triggering dissociation of the GTP-bound Gα subunit from the Gβγ pair—both of which then interact with various targets, such as enzymes and ion channels in the plasma membrane, which relay the signal onward (Figure 15–23). The α subunit is a GTPase and becomes inactive when it hydrolyzes its bound GTP to GDP. The time required for GTP hydrolysis is usually short because the GTPase activity is greatly enhanced by the binding of the α subunit to a second protein, which can be either the target protein or a specific regulator of G protein signaling (RGS). RGS proteins act as α-subunit-specific GTPase-activating proteins (GAPs) (see Figure 15–8), and they help shut off G-protein-mediated responses in all eukaryotes. There are about 25 RGS proteins encoded in the human genome, each of which interacts with a particular set of G proteins. Figure 15–21 A G-protein-coupled receptor (GPCR). (A) GPCRs that bind small ligands such as adrenaline have small extracellular domains, and the ligand usually binds deep within the plane of the membrane to a site that is formed by amino acids from several transmembrane segments. GPCRs that bind protein ligands have a large extracellular domain (not shown here) that contributes to ligand binding. (B) The structure of the β2-adrenergic receptor, a receptor for the neurotransmitter adrenaline, illustrates the typical cylindrical arrangement of the seven transmembrane helices in a GPCR.(PDB code: 3P0G.)Some G Proteins Regulate the Production of Cyclic AMP
Cyclic AMP (cAMP) acts as a second messenger in some signaling pathways.An extracellular signal can increase cAMP concentration more than twentyfold in seconds (Figure 15–24).As explained earlier (see Figure 15–14), such a rapid response requires balancing a rapid synthesis of the molecule with its rapid breakdown or removal. |
It has been argued that nearly all vascular interventional procedures lead to plaque fracture and release of microemboli, but clinical manifestations develop only in a fraction of these.Most clinical atheroembolic events follow angiographic procedures, often of the coronary vessels.Renal revascularization is now often reserved for patients failing medical therapy or developing additional complications. Techniques of renal revascularization are improving. With experienced operators, major complications occur in about 9% of cases, including renal artery dissection, capsular perforation, hemorrhage, and occasional atheroembolic disease. Although not common, atheroembolic disease can be catastrophic and accelerate both hypertension and kidney failure, precisely the events that revascularization is intended to prevent. Although renal blood flow usually can be restored by endovascular stenting, recovery of renal function is limited to about 25% of cases, with no change in 50% and some deterioration evident in others. Patients with rapid loss of kidney function, sometimes associated with antihypertensive drug therapy, or with vascular disease affecting the entire functioning kidney mass are more likely to recover function after restoring blood flow. When hypertension is refractory to effective therapy, revascularization offers real benefits. Table 299-2 summarizes currently accepted guidelines for considering renal revascularization. Emboli to the kidneys arise most frequently as a result of cholesterol crystals breaking free of atherosclerotic vascular plaque and lodging in downstream microvessels. Most clinical atheroembolic events follow angiographic procedures, often of the coronary vessels. It has been argued that nearly all vascular interventional procedures lead to plaque fracture and release of microemboli, but clinical manifestations develop only in a fraction of these.longer life spans.Atheroembolic renal disease is suspected in more 1629 than 3% of elderly subjects with end-stage renal disease (ESRD) and is likely underdiagnosed.It is more frequent in males with a history of diabetes, hypertension, and ischemic cardiac disease.Atheroemboli in the kidney are strongly associated with aortic aneurysmal disease and renal artery stenosis. |
Therefore, many developing countries are actively build-ing capacity and capability to provide the full spectrum of modern surgical care locally.158As economies improve and the benefits of laparoscopic surgery for resource-poor areas become better delineated, patients and doctors, surgical societies, ministries of health, and industries are demanding the benefits of minimally invasive surgery for patients and communities.150,159-165 The economic impact of laparoscopy may be even greater in LMICs than in developed countries.166 Worldwide, surgeons have identified laparoscopic training as one of their greatest needs. In a 2010 survey, developing laparoscopic and endoscopic skills were identified as the most important skills desired by surgeons from the West Africa College of Surgeons (WACS) (Fig. 49-32).167Transplantation is another area of great interest to people in poor countries partly because of the high prevalence of kidney failure and because chronic dialysis facilities are limited. Hepatoma and liver failure are very common in countries with a strong prevalence of hepatitis B and C. Transplantation has become the treatment of choice for end-stage kidney disease in developed countries as it dramatically improves the qual-ity of life and increases survival rates compared to medical management.168 Yet, transplantation eludes most of the developing world. Initial attempts to transport critically ill patients from LMICs to developed countries for kidney transplantation were cost-prohibitive.169 With the alarming increase in the rate at which young people have been presenting with kidney disease in developing countries, the increased utilization placed on the few dialysis machines has been overwhelming.170 Dialysis units which previously were utilized three times a week, now oper-ate 24 hours a day, 7 days a week, and cannot begin to provide the needed services to the multitudes needing treatment.Laparoscopic cholecystectomy expanded to 17 of 21 provinces in Mongolia by 2016.(Data from Raymond Price via personal communication with Dr. Erdene Sergelen.Illustration reproduced with permission from Intermountain Healthcare. |
Agent-based approaches are computationally demanding but have the potential to generate highly lifelike simulations of real biological systems.As we have seen, such models can provide useful insights, particularly in the detailed mechanistic analysis of small regulatory circuits. However, other types of computational approaches are also needed to comprehend the great complexity of cell behavior. Stochastic models, for example, attempt to account for the very important problem of random variability in molecular networks. These models do not provide deterministic predictions about the behavior of molecules; instead, they incorporate random variation into molecule numbers and interactions, and the purpose of these models is to obtain a better understanding of the probability that a system will exist in a certain state over time. Numerous other modeling strategies have been or are being developed. Boolean networks are used for the qualitative analysis of complex gene regulatory networks containing large numbers of interacting components. In these models, each molecule is a node that can exist in either the active or inactive state, thereby affecting the state of the nodes it is linked to. Models of this sort provide insights into the flow of information through a network, and they were useful in helping us understand the complex gene regulatory network that controls the early development of the sea urchin (see Figure 7–43). Boolean networks therefore reduce complex networks to a highly simplified (and potentially inaccurate) form. At the other extreme are agent-based simulations, in which thousands of molecules (or “agents”) in a system are modeled individually, and their probable behaviors and interactions with each other over time are calculated on the basis of predicted physical and chemical behaviors, often while taking stochastic variation into account. Agent-based approaches are computationally demanding but have the potential to generate highly lifelike simulations of real biological systems.Other branches of the subject are no less important for biologists.Statistics—the mathematics of probabilistic processes and noisy datasets—is an inescapable part of every biologist’s life.This is true in two main ways.First, imperfect measurement devices and other errors generate experimental noise in our data. |
Diseases associated with serous/exudative retinal detachment include severe systemic hypertension, dural arteriovenous shunt, retinal vascular anomalies, hyperviscosity syndromes, papilledema, posterior uveitis, scleritis, orbital inflammation, and intraocular neoplasms such as choroidal melanoma, choroidal metastasis, lymphoma, and multiple myeloma.Associated conditions include infantile cystinosis, primary hyperoxaluria, secondary oxalosis, Sjögren-Larson syndrome, intravenous drug abuse (talc retinopathy), and drugs such as tamoxifen, canthaxanthin, nitrofurantoin, methoxyflurane, and ethylene glycol. Crystals may also be seen in primary retinal diseases such as juxtafoveal telangiectasia, gyrate atrophy, and Bietti’s crystalline degeneration. Old microemboli may mimic retinal crystals. Vascular sheathing appears as a yellow-white cuff surrounding a retinal artery or vein (Fig. 40e-8). Diseases associated with retinal vascular sheathing include sarcoidosis, tuberculosis, toxoplasmosis, syphilis, HIV, retinitis (cytomegalovirus, herpes zoster, and herpes simplex), Lyme disease, cat-scratch disease, multiple sclerosis, chronic leukemia, amyloidosis, Behçet’s disease, retinal vasculitis, retinal vascular occlusion, and chronic uveitis. FIgURE 40e-8 Vascular sheathing over the optic disc in a patient with neurosarcoidosis. Retinal detachment is the separation of the retina from the underlying RPE. There are three main types: (1) serous/exudative, (2) tractional, and (3) rhegmatogenous retinal detachment. In serous retinal detachment, the location of the subretinal fluid is position-dependent, characteristically gravitating to the lowermost part of the fundus (shifting fluid sign), and retinal breaks are absent. Diseases associated with serous/exudative retinal detachment include severe systemic hypertension, dural arteriovenous shunt, retinal vascular anomalies, hyperviscosity syndromes, papilledema, posterior uveitis, scleritis, orbital inflammation, and intraocular neoplasms such as choroidal melanoma, choroidal metastasis, lymphoma, and multiple myeloma.The retina in the area of detachment is immobile and concaved internally.Fibrovascular proliferation is a frequent associated finding.Conditions associated with tractional retinal detachment include vascular proliferative retinopathies such as severe proliferative diabetic retinopathy, branch retinal vein occlusion, sickle cell retinopathy, and retinopathy of prematurity. |
This is because single base-pair changes do not always result in a nonfunctional protein.Some test results, especially when a single base-pair change (missense mutation) is identified, may be difficult to interpret.Overall, the false-negative rate for BRCA mutation testing is <5%.If results of that test are negative, it may then be appropriate to fully analyze the BRCA1 and BRCA2 genes.A positive test result is one that discloses the presence of a BRCA mutation that interferes with translation or function of the BRCA protein. A woman who carries a deleterious mutation has a breast cancer risk of up to 85% (in some families) as well as a greatly increased risk of ovarian cancer. A negative test result is interpreted according to the individual’s personal and family history, especially whether a mutation has been previously iden-tified in the family, in which case the woman is generally tested only for that specific mutation. If the mutation is not present, the woman’s risk of breast or ovarian cancer may be no greater than that of the general population. In addition, no BRCA muta-tion can be passed on to the woman’s children. In the absence of a previously identified mutation, a negative test result in an affected individual generally indicates that a BRCA mutation is not responsible for the familial cancer. However, the possibil-ity remains of an unusual abnormality in one of these genes that cannot yet be identified through clinical testing. It also is possible that the familial cancer is indeed caused by an identifi-able BRCA mutation but that the individual tested had sporadic cancer, a situation known as phenocopy. This is especially pos-sible if the individual tested developed breast cancer close to the age of onset of the general population (age 60 years or older) rather than before age 50 years, as is characteristic of BRCA mutation carriers. Overall, the false-negative rate for BRCA mutation testing is <5%. Some test results, especially when a single base-pair change (missense mutation) is identified, may be difficult to interpret. This is because single base-pair changes do not always result in a nonfunctional protein.In communicating indeterminate results to women, care must be taken to relay the uncertain cancer risk associ-ated with this type of mutation and to emphasize that ongoing research might clarify its meaning.In addition, testing other family members with breast cancer to determine if a genetic variant tracks with their breast cancer may provide clarification as to its significance. |
Odd gyrations of posture with wastage of muscular energy (astasia–abasia), extreme slow motion, and dramatic fluctuations over time may be observed in patients with somatoform disorders and conversion reactions.Hysterical gait disorders are among the most spectacular encountered.Patients with myopathy or muscular dystrophy more
TABLE 32-2 fEATuRES of CEREBELLAR ATAxiA, SEnSoRy ATAxiA, AnD fRonTAL gAiT DiSoRDERS
Base of Wide-based Narrow base, Wide-based support
Stride Irregular, Regular with Short, shuffling lurching path deviation
Romberg test +/− Unsteady, falls +/−
Turns Unsteady +/− Hesitant, multistep typically exhibit proximal weakness. Weakness of the hip girdle may result in some degree of excess pelvic sway during locomotion. Alcohol intoxication is the most common cause of acute walking difficulty. Chronic toxicity from medications and metabolic disturbances can impair motor function and gait. Mental status changes may be found, and examination may reveal asterixis or myoclonus. Static equilibrium is disturbed, and such patients are easily thrown off balance. Disequilibrium is particularly evident in patients with chronic renal disease and those with hepatic failure, in whom asterixis may impair postural support. Sedative drugs, especially neuroleptics and long-acting benzodiazepines, affect postural control and increase the risk for falls. These disorders are especially important to recognize because they are often treatable. Psychogenic disorders are common in neurologic practice, and the presentation often involves gait. Some patients with extreme anxiety or phobia walk with exaggerated caution with abduction of the arms, as if walking on ice. This inappropriately overcautious gait differs in degree from the gait of the patient who is insecure and making adjustments for imbalance. Depressed patients exhibit primarily slowness, a manifestation of psychomotor retardation, and lack of purpose in their stride. Hysterical gait disorders are among the most spectacular encountered. Odd gyrations of posture with wastage of muscular energy (astasia–abasia), extreme slow motion, and dramatic fluctuations over time may be observed in patients with somatoform disorders and conversion reactions.Initial awareness of an unsteady gait often follows a fall.Stepwise evolution or sudden progression suggests vascular disease.Gait disorder may be associated with urinary urgency and incontinence, particularly in patients with cervical spine disease or hydrocephalus.It is always important to review the use of alcohol and medications that affect gait and balance. |
It is marked by late, progressive, diffusely stenosing intimal proliferation in the coronary arteries, leading to ischemic injury.Allograft arteriopathy is the single most important longterm limitation for cardiac transplantation.Both T celland antibody responses to the allograft are involved in the rejection reaction.The valvular plaques in carcinoid syndrome also are similar to lesions that occur with the administration of fenfluramine (an appetite suppressant) or ergot alkaloids (for migraine headaches); of interest, these agents either affect systemic serotonin metabolism or directly bind to hydroxytryptamine receptors on heart valves. MORPHOLOGYThecardiovascularlesionsassociatedwiththecarcinoidsyndromearedistinctive,glisteningwhite,intimal,plaquelikethickeningsontheendocardialsurfacesofthecardiacchambersandvalveleaflets(
Fig.11.31 ).Thelesionsarecomposedofsmoothmusclecellsandsparsecollagenfibersembeddedinanacidmucopolysaccharide–richmatrix.Underlyingstructuresareintact.Withright-sidedinvolvement,typicalfindingsaretricuspidinsufficiencyandpulmonicstenosis. Although permanent ventricular assist device implantation is increasingly an option for management of end-stage heart disease, cardiac transplantation remains the treatment of choice for patients with intractable heart failure. Without transplantation, medically managed end-stage heart failure carries a 50% 1-year mortality rate, and less than 10% of patients survive 5 years. Over 5000 heart transplantation procedures are performed annually worldwide, mostly for DCM and IHD. The major complications of cardiac transplantation are acute cardiac rejection and allograft arteriopathy. The immunosuppression required for allograft survival also increases the risk for opportunistic infections and certain malignancies (e.g., Epstein-Barr virus–associated lymphoma). Rejection is characterized by interstitial lymphocytic inflammation, myocyte damage and a histologic pattern similar to that seen in viral myocarditis. Both T celland antibody responses to the allograft are involved in the rejection reaction. Allograft arteriopathy is the single most important longterm limitation for cardiac transplantation. It is marked by late, progressive, diffusely stenosing intimal proliferation in the coronary arteries, leading to ischemic injury.Azaouagh A, Churzidse S, Konorza T, et al: Arrhythmogenic right ventricular cardiomyopathy/dysplasia: a review and update, Clin Res Cardiol 100:383, 2011.[An excellent look at this entity and its genetic causes.]Bruneau BG: The developmental genetics of congenital heart disease, Nature 451:943, 2008. |
However, bupropion is not thought to be effective in the treatment of the anxiety disorders and may be poorly tolerated in anxious patients.Bupropion, mirtazapine, and nefazodone are the antidepressants with the least association with sexual side effects and are often prescribed for this reason.Other factors such as the patient’s age, gender, and medical status may also guide antidepressant selection. For example, older patients are particularly sensitive to the anticholinergic effects of the TCAs. On the other hand, the CYP3A4-inhibiting effects of the SSRI fluvoxamine may make this a problematic choice in some older patients because fluvoxamine may interact with many other medications that an older patient may require. There is some suggestion that female patients may respond to and tolerate serotonergic better than noradrenergic or TCA antidepressants, but the data supporting this gender difference have not been consistent. Patients with narrow-angle glaucoma may have an exacerbation with noradrenergic antidepressants, whereas bupropion and other antidepressants are known to lower the seizure threshold in epilepsy patients. At present, SSRIs are the most commonly prescribed first-line agents in the treatment of both MDD and anxiety disorders. Their popularity comes from their ease of use, tolerability, and safety in overdose. The starting dose of the SSRIs is usually the same as the therapeutic dose for most patients, and so titration may not be required. In addition, most SSRIs are now generically available and inexpensive. Other agents, including the SNRIs, bupropion, and mirtazapine, are also reasonable first-line agents for the treatment of MDD. Bupropion, mirtazapine, and nefazodone are the antidepressants with the least association with sexual side effects and are often prescribed for this reason. However, bupropion is not thought to be effective in the treatment of the anxiety disorders and may be poorly tolerated in anxious patients.Off-label uses of bupropion include the treatment of attention deficit hyperkinetic disorder (ADHD), and bupropion is commonly combined with other antidepressants to augment therapeutic response.The primary indication for mirtazapine is in the treatment of major depression. |
It is resistant to many enzymes that inactivate gentamicin and tobramycin, and, therefore, can be used against some microorganisms resistant to the latter drugs.Amikacin is a semisynthetic derivative of kanamycin; it is less toxic than the parent molecule (Figure 45–2).These formulations result in minimal systemic absorption and are unlikely to cause systemic adverse effects.Monitoring blood levels in renal insufficiency is an essential guide to proper dosing. Tobramycin has almost the same antibacterial spectrum as gentamicin with a few exceptions. Gentamicin is slightly more active against S marcescens, whereas tobramycin is slightly more active against P aeruginosa; Enterococcus faecalis is susceptible to both gentamicin and tobramycin, but E faecium is resistant to tobramycin. Gentamicin and tobramycin are otherwise interchangeable clinically. Like other aminoglycosides, tobramycin is ototoxic and nephrotoxic. Nephrotoxicity of tobramycin may be slightly less than that of gentamicin. B. Inhaled and Ophthalmic Administration
Tobramycin is formulated in solution (300 mg in 5 mL) for inhalation for treatment of P aeruginosa lower respiratory tract infections complicating cystic fibrosis. The drug is recommended as a 300-mg dose regardless of the patient’s age or weight for administration twice daily in repeated cycles of 28 days on therapy, followed by 28 days off therapy. Serum concentrations 1 hour after inhalation average 1 mcg/mL; consequently, nephrotoxicity and ototoxicity rarely occur. Caution should be used when administering tobramycin to patients with preexisting renal, vestibular, or hearing disorders. Tobramycin is also available as 0.3% ophthalmic ointment and drops for the treatment of superficial eye infections. These formulations result in minimal systemic absorption and are unlikely to cause systemic adverse effects. Amikacin is a semisynthetic derivative of kanamycin; it is less toxic than the parent molecule (Figure 45–2). It is resistant to many enzymes that inactivate gentamicin and tobramycin, and, therefore, can be used against some microorganisms resistant to the latter drugs.After injection of 500 mg of amikacin every 12 hours (15 mg/kg/d) intramuscularly, peak levels in serum are 10–30 mcg/mL.Strains of multidrug-resistant Mycobacterium tuberculosis, including streptomycin-resistant strains, are usually susceptible to amikacin.Kanamycin-resistant strains may be cross-resistant to amikacin. |
Proteinuria may also be found for 2 or 3 days after a subarachnoid hemorrhage or with high fever.A specimen of urine is obtained by catheter for determination of specific gravity and for glucose, acetone, and protein content.These screening procedures vary widely between hospitals and certain toxins must be specifically sought.The syndrome of acute hydrocephalus, most often from subarachnoid hemorrhage or from obstruction of the ventricular system by a tumor in the posterior fossa, induces a state of abulia (slowed responsivity), followed by stupor, and then coma with bilateral Babinski signs. The pupils are small and the tone in the legs is usually increased or there may be extensor posturing. The signs of hydrocephalus may be accompanied by headache and systemic hypertension, mediated through raised intracranial pressure. Chapter 29 discusses this subject further. Laboratory Procedures for the Diagnosis
Unless the cause of coma is established at once by history and physical examination, it becomes necessary to carry out a number of laboratory procedures. In patients with signs of raised intracranial pressure or indications of brain displacements, CT scan or MRI should be obtained as the primary procedure. As discussed in Chap. 2, lumbar puncture, although carrying a small risk of promoting further herniation, is nevertheless necessary in some instances to exclude bacterial meningitis or encephalitis. If poisoning or drug overdosage is suspected, aspiration and analysis of the gastric contents are sometimes helpful, but greater reliance should be placed on chromatographic analysis of the blood and urine (“toxic screen”). Accurate means are available for measuring the blood concentrations of most antiepileptic drugs, opiates, diazepines, barbiturates, alcohol, and a wide range of other toxic substances. These screening procedures vary widely between hospitals and certain toxins must be specifically sought. A specimen of urine is obtained by catheter for determination of specific gravity and for glucose, acetone, and protein content. Proteinuria may also be found for 2 or 3 days after a subarachnoid hemorrhage or with high fever.Blood counts should be obtained and in malarial districts, a blood smear should be examined for parasites.Neutrophilic leukocytosis occurs in bacterial infections and mild elevations of the white blood cell counts also with brain hemorrhage and infarction, although rarely exceeding 12,000/mm3. |
Indeed, the diagnosis of angina should be suspect if it does not respond to the combination of these measures.Exertional angina typically is relieved in 1–5 min by slowing or ceasing activities and even more rapidly by rest and sublingual nitroglycerin (see below).Angina may also be precipitated by unfamiliar tasks, a heavy meal, exposure to cold, or a combination of these factors.The patient may be awakened at night by typical chest discomfort and dyspnea. Nocturnal angina may be due to episodic tachycardia, diminished oxygenation as the respiratory pattern changes during sleep, or expansion of the intrathoracic blood volume that occurs with recumbency; the latter causes an increase in cardiac size (end-diastolic volume), wall tension, and myocardial oxygen demand that can lead to ischemia and transient left ventricular failure. The threshold for the development of angina pectoris may vary by time of day and emotional state. Many patients report a fixed threshold for angina, which occurs predictably at a certain level of activity, such as climbing two flights of stairs at a normal pace. In these patients, coronary stenosis and myocardial oxygen supply are fixed, and ischemia is precipitated by an increase in myocardial oxygen demand; they are said to have stable exertional angina. In other patients, the threshold for angina may vary considerably within any particular day and from day to day. In such patients, variations in myocardial oxygen supply, most likely due to changes in coronary vasomotor tone, may play an important role in defining the pattern of angina. A patient may report symptoms upon minor exertion in the morning (a short walk or shaving) yet by midday be capable of much greater effort without symptoms. Angina may also be precipitated by unfamiliar tasks, a heavy meal, exposure to cold, or a combination of these factors. Exertional angina typically is relieved in 1–5 min by slowing or ceasing activities and even more rapidly by rest and sublingual nitroglycerin (see below). Indeed, the diagnosis of angina should be suspect if it does not respond to the combination of these measures.Its impact on the patient’s functional capacity can be described by using the New York Heart Association functional classification (Table 293-1).I Patients have cardiac disease but without the resulting limitations of physical activity.Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. |
Moreover, chronic use of PCP may lead to an irreversible schizophrenia-like psychosis.Flashbacks of altered perception can occur years after LSD use.Hallucinogens and NMDA antagonists, even if they do not produce dependence or addiction, can still have long-term effects.Lysergic acid diethylamide (LSD), for example, activates the serotonin 5-HT2A receptor in the prefrontal cortex, enhancing glutamatergic transmission onto pyramidal neurons. These excitatory afferents mainly come from the thalamus and carry sensory information of varied modalities, which may constitute a link to enhanced perception. Phencyclidine (PCP) and ketamine produce a feeling of separation of mind and body (which is why they are called dissociative anesthetics) and, at higher doses, stupor and coma. The principal mechanism of action is a use-dependent inhibition of glutamate receptors of the NMDA type. High doses of dextromethorphan, an over-the-counter cough suppressant, can also elicit a dissociative state. This effect is mediated by a rather nonselective action on serotonin reuptake, and opioid, acetylcholine, and NMDA receptors. The classification of NMDA antagonists as nonaddictive drugs was based on early assessments, which, in the case of PCP, have recently been questioned. In fact, animal research shows that PCP can increase mesolimbic dopamine concentrations and has some reinforcing properties in rodents. Concurrent effects on both thalamocortical and mesolimbic systems also exist for other addictive drugs. Psychosis-like symptoms can be observed with cannabinoids, amphetamines, and cocaine, which may reflect their effects on thalamocortical structures. For example, cannabinoids, in addition to their documented effects on the mesolimbic dopamine system, also enhance excitation in cortical circuits through presynaptic inhibition of GABA release. Hallucinogens and NMDA antagonists, even if they do not produce dependence or addiction, can still have long-term effects. Flashbacks of altered perception can occur years after LSD use. Moreover, chronic use of PCP may lead to an irreversible schizophrenia-like psychosis.The first group contains the opioids, cannabinoids, f-hydroxybutyric acid (GHB), and the hallucinogens, which all exert their action through Gio protein-coupled receptors.The second group includes nicotine, alcohol, the benzodiazepines, dissociative anesthetics, and some inhalants, which interact with ionotropic receptors or ion channels. |
In the case of ethylene glycol, oxaluria and acidosis are additional factors that may precipitate treatment.Generally, for either methanol or ethylene glycol, a plasma level of the alcohol above 20 mg/dL, or above 10 mg/dL when combined with an osmolal gap over 10 is considered appropriate to institute the drug.(The anion gap has been defined in different ways, but the most convenient is the difference between the positive ion Na+ and the sum of negative ions, Cl− plus HCO3− [venous CO2 is used for the latter]; a value greater than 12 is considered a gap.) The cause of the renal toxicity is less clear—probably it is a result of the formation of oxalate from glycolate and the deposition of oxalate crystals in renal tubules. (One of our recent patients had hippurate crystals in the urine, a finding that is more characteristic of toluene ingestions.) These crystals appear in the urine and sometimes in the cerebrospinal fluid and aid in diagnosis. Treatment of Nonethanol Alcohol Intoxication
The treatment of ethylene glycol poisoning has, until relatively recently, consisted of hemodialysis and the intravenous infusion of sodium bicarbonate and ethanol, the latter serving as a competitive substrate for ADH. However, the use of ethanol in this regimen is problematic. Baud and colleagues, and more recently Brent and colleagues and Jacobsen, have advocated the use of intravenous 4- methylpyrazole (fomepizole), which is a far more effective inhibitor of ADH than is alcohol. They recommend this form of treatment for methanol poisoning as well. Information from the American Academy of Toxicology is cited in a review of the use of fomepizole by Brent, which is recommended to the interested reader. Generally, for either methanol or ethylene glycol, a plasma level of the alcohol above 20 mg/dL, or above 10 mg/dL when combined with an osmolal gap over 10 is considered appropriate to institute the drug. In the case of ethylene glycol, oxaluria and acidosis are additional factors that may precipitate treatment.Some patients who recover from the acute renal and metabolic effects are left with multiple cranial nerve defects, particularly of the seventh and eighth nerves.The latter abnormalities develop 6 to 18 days after the ingestion of ethylene glycol and have been attributed to the deposition of oxalate crystals along the cisternal portions of the affected nerves (Spillane et al). |
They are transmitted by direct contact or by fomites and have an incubation period of approximately 1 month before clinical presentation.They occur frequently in school-age children, with a prevalence of 4% to 20%.Common warts (verruca vulgaris),associated with HPV types 1 and 2, are the most common form (71%).Warts occur at all ages.Cutaneous HSV infection in persons with an underlying skin disorder (e.g., atopic dermatitis) can result in eczema herpeticum (Kaposi varicelliform eruption), a disseminated cutaneous infection. There may be hundreds of herpetic vesicles over the body, usually concentrated in the areas of skin affected by the underlying disorder. Treatment with oral valacyclovir or famciclovir may shorten duration of disease for primary and recurrent infection. Prophylactic antiviral therapy may be warranted in those with frequent recurrences. Infants, persons with eczema, and persons with immunodeficiency are at increased risk for disseminated and severe HSV disease and should receive intravenous acyclovir therapy. Available @ StudentConsult.com
Warts are caused by the human papillomaviruses (HPVs),nonenveloped, double-stranded DNA viruses that infect skin and mucous membrane keratinocytes. More than 100 HPV serotypes have been identified, with different serotypes accounting for the variation in location and clinical presentations. There are 15 to 20 oncogenic (high-risk) types, including 16, 18, 31, 33, 35, 39, 45, 51, 52, and 58. HPV types 16 and 18 are associated with 70% of cases of cervical cancer as well as vulvar and vaginal cancers. Common nononcogenic (low-risk) types include 1, 2, 3, 6, 10, 11, 40, 42, 43, 44, and 54. Regardless of the infecting serotype, all warts are associated with hyperplasia of the epidermal cells. Warts occur at all ages. Common warts (verruca vulgaris),associated with HPV types 1 and 2, are the most common form (71%). They occur frequently in school-age children, with a prevalence of 4% to 20%. They are transmitted by direct contact or by fomites and have an incubation period of approximately 1 month before clinical presentation.They also may be found on the nose, ears, and lips.Filiform warts are verrucous, exophytic, 2-mm papules that have a narrow or pedunculated base.Flat warts (verruca plana) are associated with HPV types 3 and 10 and are multiple, flat-topped 2to 4-mm papules clustered on the dorsal surface of the hands, on the soles of the feet (plantar warts), or on the face. |
The VHL protein is a component of a ubiquitin E3 ligase.SDH is an enzyme of the Krebs cycle and the mitochondrial respiratory chain.Biallelic gene inactivation has been demonstrated for the VHL, NF1, and SDH genes, whereas RET mutations activate receptor tyrosine kinase activity.The classic “rule of tens” for pheochromocytomas states that ∼10% are bilateral, 10% are extra-adrenal, and 10% are malignant. Pheochromocytomas and paragangliomas are well-vascularized tumors that arise from cells derived from the sympathetic (e.g., adrenal medulla) or parasympathetic (e.g., carotid body, glomus vagale) paraganglia (Fig. 407-1). The name pheochromocytoma reflects the black-colored staining caused by chromaffin oxidation of catecholamines; although a variety of terms have been used to describe these tumors, most clinicians use this designation to describe symptomatic catecholamine-producing tumors, including those in extra-adrenal retroperitoneal, pelvic, and thoracic sites. The term paraganglioma is used to describe catecholamine-producing tumors in the skull base and neck; these tumors may secrete little or no catecholamine. In contrast to common clinical parlance, the World Health Organization (WHO) restricts the term pheochromocytoma to adrenal tumors and applies the term paraganglioma to tumors at all other sites. The etiology of sporadic pheochromocytomas and paragangliomas 2329 is unknown. However, 25–33% of patients have an inherited condition, including germ-line mutations in the classically recognized RET, VHL, NF1, SDHB, SDHC, and SDHD genes or in the more recently recognized SDHA, SDHAF2, TMEM127, and MAX genes. Biallelic gene inactivation has been demonstrated for the VHL, NF1, and SDH genes, whereas RET mutations activate receptor tyrosine kinase activity. SDH is an enzyme of the Krebs cycle and the mitochondrial respiratory chain. The VHL protein is a component of a ubiquitin E3 ligase.Its clinical presentation is so variable that pheochromocytoma has been termed “the great masquerader” (Table 407-1).Among the presenting manifestations, episodes of palpitation, headache, and profuse sweating are typical, and these manifestations constitute a classic triad.The presence of all three manifestations in association with hypertension makes pheochromocytoma a likely diagnosis. |
None of these theories has been corroborated, and none ever gained wide acceptance, particularly as the biological disease model of schizophrenia, propelled by successful pharmacologic treatment, defined a disease and not a psychological disorder.This was an improvement insofar as the term dementia was already being used to specify the clinical effects of another category of disease; unfortunately, however, the new name implied a “split personality” or “split mind.” By the “splitting” of psychic functions, Bleuler meant the lack of correspondence between ideation and emotional display—the inappropriateness of the patient’s affect in relation to his thoughts and behavior. In contrast, in bipolar disease, the patient’s mood and affect accurately express his morbid thoughts. Bleuler also introduced the term autism (“thinking divorced from reality”) as an aspect of the thought disorder. Bleuler believed that all the schizophrenic syndromes were composed of primary or basic symptoms, summarized by subsequent authors as the “four A’s” (loose associations, flat affect, ambivalence, and autism) and of secondary or “partial phenomena” such as delusions, hallucinations, negativism, and stupor. However interesting this formulation proved to be, the psychologic abnormalities are so difficult to define precisely that these divisions have come to be of only mnemonic value. Meyer, who introduced the “psychobiologic approach” to psychiatry, sought the origins of schizophrenia, as well as other psychiatric syndromes, in the personal and medical history of patients, emphasizing particularly their habitual reactions to life events. Freud viewed schizophrenia as a manifestation of a “weak ego” and an inability to control anxiety and instinctual forces—the result of a fixation of libido at an early (“narcissistic”) stage of psychosexual development. None of these theories has been corroborated, and none ever gained wide acceptance, particularly as the biological disease model of schizophrenia, propelled by successful pharmacologic treatment, defined a disease and not a psychological disorder.The separation of behaviors into “positive” and “negative” symptoms was believed to be useful in distinguishing among the types of schizophrenias and perhaps to align the mental status with conventional physiologic analysis, but this view is an oversimplification, as pointed out by Andreasen. |