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Only 60–90% of de novo synthesized osteocalcin is incorporated into the bone matrix binding to hydroxy apa- tite during matrix mineralization order 30 gr rumalaya gel otc. The remainder enters the circulation where it may be assayed as a sensitive marker for bone formation cheap rumalaya gel on line. Serum osteocalcin is derived almost exclu- sively from bone formation discount rumalaya gel online amex, rather than resorption. Serum osteocalcin is increased in diseases marked by elevated bone turnover, such as osteoporosis, hyperparathyroidism, and Paget disease, and is decreased in conditions associated with low bone turnover, including hypoparathyroidism and growth hormone defciency. P63 (ap53 Homolog at 3q27–29) Ab-4 (cocktail) mouse (b) monoclonal antibody recognizes a 63-kDa protein, identi- fed as p63. Protein p63 shows remarkable struc- Osteocalcin antibody: An osteocalcin/matrix Gla protein tural similarity to p53 and to the related p73 gene. This 49-amino p53, the p63 gene encodes multiple isotypes with remarkable acid single-chain vitamin K-dependent protein synthesized divergent abilities to transactivate p53 reporter genes and by fbroblasts is a principal constituent of the noncollag- induce apoptosis. K-dependent carboxylase yields three gamma carboxyglu- tamic acid residues at positions 17, 21, and 24, affording it a Antiprogesterone receptor antibody is a mouse monoclo- nal antibody against human progesterone receptor. A mouse monoclonal antihuman progesterone receptor antibody that specifcally recognizes the A and B forms of the receptor in Western blot purifed recombinant receptor, normal endo- metrium, and cell lysates of the progesterone receptor-rich T47D human breast carcinoma cell line. No cross-reactivity was found with androgen receptor, estrogen receptor, or glu- cocorticoid receptor. The antibody binds an epitope found between amino acids 165 and 534, in the N-terminal trans- activation domain of the progesterone receptor molecule. Various tumors of the female reproductive tract have been shown to express progesterone receptor. Antihuman thyroglobulin is a rabbit antibody that reacts with human thyroglobulin. It can also be used to differentiate small-cell lung carcinoma from lymphoid infltrates. Increased levels suggest a benign or malignant liver lesion, a carcinoma of the yolk sac, as well as selected other tumors. It has been detected in yolk sac carcinomas of gonadal and extragonadal occasions, hepatic neoplasia, and selected other neoplasms. It cross- infected liver cells, although variable staining may also be reacts with luteinizing hormone. This antibody staining is predominantly intranuclear necrotizing encephalitis and can be found in the temporal lobe in a focal or diffuse pattern, although perinuclear cytoplasmic of an infected brain. The anti- coma tissue, primarily effusion lymphoma and multi-centric body shows no cross-reactivity with other herpesviruses or Castleman disease using the polymerase chain reaction and adenoviruses. It is identi- latent nuclear antigen protein demonstrable by the immu- fed using a four-mouse monoclonal antibody cocktail, which noperoxidase technique. The structural antigens on this virus can be detected in a noblasts in infectious mononucleosis. In surgical pathologic diagnosis, monoclonal antibodies against desmin are useful in identifying muscle tumors. Desmin (D33), mouse: Desmin antibody detects a protein that is expressed by cells of normal smooth, skeletal, and cardiac muscles. The light microscope has suggested that desmin is primarily located at or near the periphery of Z lines in striated muscle fbrils. In smooth muscle, desmin inter- connects cytoplasmic dense bodies with membrane-bound dense plaques. Desmin antibody reacts with leiomyomas, rhabdomyomas, and perivascular cells of glomus tumors of the skin (if they are of myogenic nature). Parvovirus B19 infection should be antigens located in the cytoplasm of myocytic cells. It also is positive in Actin the principal muscle protein, which together with breast ducts, sweat and salivary glands, bronchial glands and myosin causes muscle contraction, is used in surgical pathol- Schwann cells, serous acini, malignant melanomas, myoepi- ogy as a marker for the identifcation of tumors of muscle thelium, and neurofbrosarcomas. Actin is identifed through immunoperoxidase stain- ing of surgical pathology tissue specimens. The ronal cells as chondrocytes and histiocytes are also S-100 antibody is intended for qualitative staining in sections of positive. Antimuscle actin antibody specifcally binds to antigens located in the cyto- S-100 protein antibody is a mouse monoclonal antibody plasmic regions of normal muscle cells. Unexpected antigen specifc for S-100 protein that is found in normal melanocytes; expression or loss of expression may occur, especially in neo- Langerhans cells; histiocytes; chrondrocytes; lipocytes; skel- plasms. Occasionally, stromal elements surrounding heav- etal and cardiac muscle; Schwann cells; epthelial and myo- ily stained tissue and/or cells will show immunoreactivity. Neoplasms derived from these cells also express logical studies and the evaluation of appropriate controls. A large number of well- differentiated tumors of the salivary gland, adipose and car- Myogenin (F5D), mouse: Anti-myogenin monoclonal anti- tilaginous tissue, and Schwann cell-derived tumors express body labels the nuclei of myoblasts in developing muscle S-100 protein. Almost all malignant melanomas and cases tissue and is expressed in tumor cell nuclei of rhabdomyosar- of histiocytosis X are positive for S-100 protein. Positive nuclear staining may occur in Wilms’ tumor, fact that S-100 protein is a ubiquitous substance, its demon- as well as in some myopathies. Myoglobin is an oxygen-storing muscle protein that serves as a marker of muscle neoplasms, demonstrable by immu- Antihuman α-smooth muscle actin is a mouse monoclo- noperoxidase staining for surgical pathologic diagnosis. The antibody reacts with smooth muscle cells of vessels Myoglobin antibody is a reagent that stains normal striated and different parenchyma without exception, but with differ- muscle and striated muscle-containing tumor. Using immu- ent intensity, according to the amount of α-smooth muscle nohistochemical procedures on formalin-fxed, paraffn- actin present in smooth muscle cells, myoepithelial cells, peri- embedded tissues, this antibody stains human skeletal and cytes, and some stromal cells in the intestine, testes, breast, cardiac muscle. The antibody also reacts with myofbroblasts in 880 Atlas of Immunology, Third Edition benign and reactive fbroblastic lesions and perisinusoidal Anti-bcl-2 primary antibody is a mouse monoclonal anti- cells of normal and diseased human livers. The bcl-2 oncoprotein expression is inhibited in ger- minal centers where apoptosis forms a part of the B cell Vimentin is a 55-kDa intermediate flament protein syn- production pathway. In 90% of follicular lymphomas, a trans- thesized by mesenchymal cells such as vascular endothelial location occurs which justaposes the bcl-2 gene at 19q21 to cells, smooth muscle cells, histiocytes, lymphocytes, fbro- an immunoglobulin gene, with subsequent deregulation of blasts, melanocytes, osteocytes, chondrocytes, astrocytes, protein synthesis and cell proliferation. Distinction example, immunoperoxidase staining may reveal vimen- of follicular hyperplasia from follicular lymphoma is a com- tin and cytokeratin in breast, lung, kidney, or endometrial mon problem in histopathology. Reactive follicles show no adenocarcinomas staining for bcl-2, whereas the cells in neoplastic follicles exhibit membrane staining. Antivimentin antibody is a mouse monoclonal antibody raised against purifed bovine eye lens vimentin.
Some neurologists have agabine discount rumalaya gel 30gr without a prescription, more than two daily administrations may be required to also in the past favoured the use of relatively high initial mainte- minimize excessive fuctuations in plasma concentration rumalaya gel 30 gr without a prescription. This is nance dosages out of a fear that a delay in achieving complete sei- especially important for individuals in whom half-lives are at the zure control might increase the probability of the epilepsy becom- shorter end of the spectrum buy 30gr rumalaya gel with visa, such as children and enzyme-induced ing intractable. With these drugs, intermittent adverse efects are for most of the epilepsy syndromes, there is no evidence that this not uncommon at the time of peak drug concentration, whereas is the case. More than twice-daily dosing may similarly be Frequency of administration required for gabapentin, which also has a short half-life and, ad- For most antiepileptic drugs, attainment of an adequate response is ditionally, is absorbed from the intestine by a saturable transport dependent on the persistence of efcacious drug concentrations at mechanism (see Chapter 36). Because the concentration at the site high dosages, utilizing multiple daily administrations of gabapen- of action is in equilibrium with the concentration in plasma, a dos- tin provides a strategy to improve the oral absorption of the drug. Tese are discussed briefy in the next rate of absorption of the drug and its elimination half-life (see Chap- section of this chapter. With rapidly absorbed compounds, it is a good general rule In some individuals, even drugs with short half-lives such as gab- to choose a dosing interval that is no greater than the half-life of the apentin and tiagabine may still produce adequate responses with drug. Drugs with a slow elimination rate such as phenobarbital may a twice-daily schedule. This may be explained, at least in part, by be given once daily at bedtime, but most other antiepileptic drugs pharmacodynamic variability (i. The optimal frequency of may tolerate well high peak plasma drug levels or, conversely, main- administration may also vary depending on pharmacokinetic pat- tain a good response at low trough concentrations). For example, lamotrigine should be there is also evidence that a dissociation exists between their con- given twice daily in individuals taking concomitant enzyme-induc- centration profle in plasma and the duration of efect. For example, ing antiepileptic drugs (due to its relatively short half-life in these levetiracetam is recommended for use on a twice-daily schedule individuals), but it may be given once daily in adults receiving no despite a plasma half-life of about 7 h. In the case of vigabatrin, comedication, and, even more appropriately, in those comedicated which also has a plasma half-life of about 7 h, even once-daily General Principles of Medical Management 117 dosing might be appropriate because its action involves irrevers- viduals. Tere is some In recent years, a number of reports have highlighted the possibili- evidence that valproic acid also has a longer duration of action than ty of adverse clinical outcomes following generic substitution , expected from its half-life , and once-daily dosing of valproate although this is not confrmed in all studies , and evidence is feasible in many individuals, particularly when a sustained-re- from long-term well-designed randomized controlled trials on this lease formulation is used. In view of these considerations, there is gen- recommended in women of child-bearing potential, because ani- eral agreement that any switch between pharmaceutical products mal studies suggest that teratogenic efects may be enhanced at high of antiepileptic drugs should be approved by the physician, that peak plasma concentrations of the drug . Greater concerns apply to countries in For individuals stabilized on chronic treatment, tablets or capsules which regulatory control of the quality of pharmaceuticals is less should be preferred to syrups, whenever possible, because they strict, particularly low-income countries . Monitoring plasma allow more precise dosing, avoid the efect of tooth-damaging in- concentrations can be useful for rapid detection of potential chang- gredients such as sucrose, and minimize the risk of adverse efects es in plasma drug concentration when switching formulations. Nearly all children Sometimes it is desirable to modify a drug’s rate and extent of above the age of 5 years can cope with conventional solid dosage absorption in order to obtain a more favourable plasma concentra- forms. In particular, for drugs that are absorbed and eliminated fants and younger children (e. The type of formulation infuences are designed to prolong the absorption, produce a smoother drug the rate of drug delivery to the bloodstream and, hence, to the site of concentration profle and allow less frequent dosing . Enteric-coated tablets, such as those utilized in some formu- fed-release products are currently available for carbamazepine, val- lations of valproic acid, can be absorbed only afer the tablet reaches proic acid, phenytoin, lamotrigine, oxcarbazepine, topiramate and the intestine, and therefore absorption shows a lag-time related to levetiracetam. Typically, the passage of enteric-coated twice daily, and some are also suitable for once-daily dosing. With tablets to the intestine is delayed by the concomitant ingestion of once-daily dosing, however, the advantages of improved conveni- food, and, therefore, when enteric-coated formulations are admin- ence should be weighed against the risks associated with a promi- istered with a meal, drug absorption may not take place for up to nent decrease in plasma drug levels should the patient forget to take many hours afer the ingestion . At least for some drugs, most notably carbamazepine, In most countries, diferent formulations of the same drug are sustained-release formulations provide clear advantages, particularly available, and some of these may difer in bioavailability. Switch- in reducing intolerability associated with excessively high peak plas- ing between products with diferent bioavailability (e. It should be noted, however, that some from a regular to a modifed-release product, or between other modifed-release formulations may difer from conventional formu- products known not to be bioequivalent) may result in a change in lations not only in rate, but also in extent of absorption. Terefore, plasma drug levels and, consequently, in loss of seizure control or an adjustment in total daily dosage may be needed when switching clinical toxicity. To minimize risks, switches between these prod- from a conventional to a modifed-release formulation or vice versa. Midazolam and fosphenytoin, on the other hand, are intake of the generic be equivalent to those measured afer intake of absorbed efciently when given intramuscularly, and a well-de- the brand . In practice, bioequivalence is established by demon- signed randomized double-blind trial found that intramuscular strating that 90% confdence limits for the ratio of key pharmacoki- midazolam compares favourably with intravenous lorazepam for netic parameters afer intake of the generic and brand product fall pre-hospital treatment of status epilepticus by paramedics . For those confdence limits to be met, the case of diazepam, the rectal route provides rapid and efcient however, mean estimates for ratios of measures of rate and extent of absorption when solutions, gels or rectal capsules are used, and can absorption must be relatively close to 100%. Tere has been consid- be utilized by non-medical personnel in selected situations, for ex- erable debate about benefts and risks associated with generic pre- ample to prevent or terminate a seizure in a febrile child. Generics bring major cost benefts to individuals dazolam, the buccal and the intranasal routes may also ensure rap- and to society, but concern has been expressed that conventional id absorption, and have been used used successfully for the acute confdence limits for bioequivalence may be too wide for some an- management of seizures (see Chapter 17) . Formulations that tiepileptic drugs, and that for such drugs even a modest reduction can be given by alternative routes of administration are also use- in plasma drug concentration afer switching to or from a generic ful to substitute for oral medication in individuals unable to take a may be sufcient to cause recurrence of seizures in occasional indi- medicine orally (e. However, According to pharmacokinetic principles, about fve half-lives dose adjustments should be based primarily on clinical response are required to reach steady-state plasma concentrations afer and individuals who are seizure-free at low plasma drug concentra- stabilizing the patient on a given dosage. Conversely, as some cannot be fully evaluated before this period, and this should be individuals may tolerate and indeed require plasma drug concen- taken into account in determining the minimum interval that trations above the upper limit of the reference range, no patient should elapse before assessing the need for dosage adjustments. The application of ther- within a few days, whereas for phenytoin and phenobarbital it apeutic drug monitoring to the individualization of therapy is dis- may take weeks for the plasma concentration to stabilize follow- cussed in detail in Chapter 10. Tere are instances of individuals who have been discharged from clinical observation too soon afer a dose Dose optimization in special situations increment and became subsequently intoxicated as a result of pro- The strategy concerning dose titration used in children is similar to gressive drug accumulation. As the initial target dose, dosage should be increased stepwise within drug clearance for most antiepileptic drugs is higher in infants and the recommended range until seizures are controlled or until intol- children than in adults , dosage requirements on a milligram erable adverse efects appear. The magnitude of dosage increments per kilogram basis are usually higher in paediatric patients than in should be determined by the steepness of the dose–response rela- adults (see Chapters 13 and 14). Conversely, newborn infants, espe- tionship, which varies between drugs, and by the individual’s re- cially when born prematurely, ofen have a reduced drug clearance sponse at the previously assessed dose. During chronic treatment taken when adjusting phenytoin dosage, because small dose incre- in children, dosage is rarely modifed based on body weight chang- ments can result in disproportionate increase in plasma drug levels es alone, and assessment of clinical response is essential in deter- (see Chapter 43). Although most physicians are aware of the need mining the need for dose adjustments . Compared with adults, for careful individualization of dosage, inadequate dosing remains children are more ofen treated with liquid dosage forms, which an important determinant of suboptimal seizure control.
T cell receptors may also eterious nature are referred to as hypersensitivity reactions identify autoantigen (self antigen) when the immune reactiv- and are subgrouped into four types purchase rumalaya gel discount. Abrogation of tolerance to self antigens often leads to auto- An autoantibody recognizes and interacts with an antigen immunity purchase rumalaya gel on line amex. This may result from altered regulation of lym- present as a natural component of the individual synthesiz- phocytes reactive with self or in aberrations in self-antigen ing the autoantibody (Figure 14 purchase rumalaya gel online. Many factors participate in the generation ability of these autoantibodies to “cross-react” with corre- of autoimmunity. Autoimmune reactants may be a conse- sponding antigens from other members of the same species quence, and not a cause, of a disease process. Autoimmune provides a method for in vitro detection of such autoanti- diseases may be organ-specifc, such as autoimmune thy- bodies. Autoallergy is a tissue injury or disease induced by roiditis, or systemic, such as systemic lupus erythemato- immune reactivity against self antigens. Helper T cells control the immune response to even though they are excellent antigens or immunogens in protein antigens. This lack of immune reactivity against self was may lead to high-affnity autoantibody production specifc believed to protect against autoimmune disease. Processes that activate antigen-presenting cells in tissues, thereby upregu- Autoagglutination is the spontaneous aggregation of eryth- lating their expression of costimulators and leading to the rocytes, microorganisms, or other particulate antigens in a formation of cytokines, may abrogate T lymphocyte anergy. The term refers also to the aggrega- involves lpr/lpr and gld/gld mice that succumb at 6 months tion of an individual’s cells by their own antibody. The lpr/lpr is associated with Autoimmune complement fxation reaction is the ability a defect in the gene that encodes Fas, which determines the of human blood serum from patients with certain autoim- molecule that induces cell death. The gld/gld is attributable mune diseases such as systemic lupus erythematosus, chronic 447 448 Atlas of Immunology, Third Edition Witebsky’s criteria: According to criteria suggested by Ernest Witebsky, an autoimmune response should be consid- Self antigen ered as the cause of a human disease if (1) it is regularly asso- Autoantibody ciated with that disease, (2) immunization of an experimental animal with the antigen from the appropriate tissue causes it to make an immune response (form antibodies or develop Processed, B allergy), (3) associated with this response the animal devel- presented ops pathological changes that are basically similar to those of Drug hapten to T cell humans, and (4) the experimental disease can be transferred or bacteria Immunocompetent or virus to self Ag to a nonimmunized animal by serum or by lymphoid cells. Autoreactive T lymphocytes in selected diseases may rep- resent a failure of normal regulation, or autoreactive T cells present in a normal healthy individual may be a necessary aspect of the immune system. Autoreactive T cells develop from mature antigen-dependent precursor cells that have changed physiologically in a manner that restores their thymic selected ability to respond to self. Any mechanism that returns T cells to a resting state would halt autoreac- tive expansion until stimulation is induced once again by a specifc foreign antigen. Cytokine autoantibodies are autoantibodies that may inhibit cytokine functions and lead to cytokine defciency. By contrast, these autoantibodies may serve as cytokine-specifc carriers in the circulation. For example, insulin autoantibodies may prolong the release of active insulin to the tissues, leading to hypoglycemia in non- diabetics and a signifcant decrease in the exogenous insulin requirement in diabetic patients. Methods for cytokine autoantibody detection include bioassays, immuno- Autoreactivity is an immune response against self metric assays, and blotting techniques. Cytoskeletal autoantibodies are specifc for cytoskel- Autosensitization is the development of reactivity against etal proteins that include microflaments (actin), microtu- one’s own antigens, i. The drug attaches to and are present in low titers in a broad spectrum of diseases cells in vivo without changing the surface antigenic makeup. These individuals, 27 to 52% in those with rheumatoid arthritis, antibodies are not helpful in diagnosis. Natural autoantibodies may appear in frst-degree relatives of Determinant spreading is an amplifcation mechanism autoimmune disease patients as well as in older individuals. They T lymphocyte response diversifes through induction of are often present in patients with bacterial, viral, or parasitic T cells against additional autoantigenic determinants. In contrast to response to the original epitope is followed by intramolecu- natural antibodies, autoantibodies may increase in disease lar spreading, activation of T lymphocytes for other cryptic and may lead to tissue injury. The blood group isohemag- or subdominant self-determinants of the same antigen during glutinins are also termed natural antibodies even though they chronic and progressive disease; intermolecular spreading are believed to be of heterogenetic immune origin as a con- involves epitopes on other unrelated self antigens. The dominant epitopes are the ones Pathologic autoantibodies are autoantibodies generated most effciently processed and presented from native antigen. Many autoantibodies are physiologic, rep- often requires no additional processing can a response to a resenting an epiphenomenon during autoimmune stimula- cryptic determinant be mounted. Subdominant determinants tion, whereas others contribute to the pathogenesis of tissue fall between these two types. Autoantibodies that lead to red blood-cell destruction in autoimmune hemolytic anemia represent pathogenic auto- Some mechanisms in drug-induced autoimmunity are sim- antibodies, whereas rheumatoid factors such as IgM anti-IgG ilar to those induced by viruses (Figure 14. Autoantibodies autoantibodies have no proven pathogenic role in rheumatoid may appear as a result of the helper determinant effect. The generalized lymphoid Sequestered antigen is anatomically isolated and not in hyperplasia also involves clones specifc for autoantigens. A contact with the immunocompetent T and B lymphoid cells of third form is that seen with α-methyldopa. When a sequestered antigen such as myelin basic protein is released by one or several mechanisms including viral infam- Drug mation, it can activate both immunocompetent T and B cells. Autoimmune diseases may be cipal mechanism in experimental and postviral encephalitis. Likewise, lens protein of the eye Autoimmune disease animal models: Studies of human that enters the circulation as a consequence of either crushing autoimmune disease have always been confronted with injury to an eye or exposure of lens protein to immunocom- the question of whether immune phenomena, including the petent cells inadvertently through surgical manipulation may production of autoantibodies, represent the cause or a conse- lead to an antilens protein immune response. The use of animal models has helped induced by sequestered antigens is relatively infrequent and to answer many of these questions. A broad Sex hormones and immunity: Females have been recog- spectrum of human autoimmune diseases has been clarifed nized as more susceptible to certain autoimmune diseases through the use of animal models that differ in detail but have than males, which immediately led to suspicion that sex nevertheless provided insight into pathogenic mechanisms, hormones might play a role. The exact mechanisms through converging pathways and disturbances of normal regulatory which sex steroids interact with the immune system remain function related to the development of autoimmunity. Female mice synthesize more antibody eases spontaneously without any experimental manipulation. Murine cell-mediated responses investigate pathogenetic mechanisms underlying disease to selected antigens were stronger in females than in males. Spontaneous animal models for organ-specifc Sex steroids have a profound effect on the thymus. Androgen autoimmune diseases include the obese strain of chickens or estrogen administration to experimental animals led to that are an animal model for Hashimoto thyroditis. Animal thymic involution, whereas castration led to thymic enlarge- strains with spontaneous insulin-dependent diabetes mellitus ment. Sex steroids have numerous targets that include the islet β cells of the pancreas. Spontaneous animal models bone marrow and thymus where the precursors of immunity of systemic autoimmune diseases include the University of originate and differentiate.