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A student is expected to answer this; otherwise it may be difficult for him to pass generic 0.18 mg levonorgestrel amex. Understand the difference in the structure of resting and activated parietal cell order levonorgestrel with visa. Controlled emptying of food: Stomach performs its major function of stomach is the storage of food generic levonorgestrel 0.18 mg on line, it regu­ own controlled emptying (gastric emptying) buy levonorgestrel 0.18mg with mastercard. It allows lates controlled emptying of food into the duodenum food to enter into duodenum and jejunum at a lesser and prepares the chyme for digestion and absorption in but controlled rate so that load on the upper part of the small intestine. Chyme results from grinding of food the small intestine is not more than the amount that it into smaller particles and mixing of food with gastric can handle. Iron is absorbed from gut only in the fer­ stomach is the temporary storage of food. Grinding and mixing of food: Stomach causes grind­ and other ingested microorganisms. The capacity of the stomach depends on age, gender only activates pepsin, but also provides acidic environ- and eating habit. These mucous and alkaline fluids protect gastric epi­ tein present in the terminal part of ileum and then thelium from acidic content and mechanical injury. Therefore, gastrectomy or the mucosal surface of stomach is studded with chronic gastric atrophy results in megaloblastic ane- gastric pits (faveola) into which gastric glands empty mia (Clinical Box 39. The gastric glands are situated deep in the mucosal ble substances, such as alcohol and few drugs. There are three causes microcytic hypochromic anemia due to iron deficiency and types of gastric glands: intrinsic factor deficiency causes megaloblastic anemia due to B12 deficiency. The cardiac glands: Located below the lower esopha­ geal sphincter and contain mainly mucous secreting cells. The oxyntic glands: Located in the fundus and body of the stomach and contain mainly the oxyntic cells. Pyloric glands: Present in the pyloric­antral region fundus, body and antrum (Fig. Esophagus opens and consist mainly of mucous neck cells that secrete into stomach through gastro-esophageal junction that mucous and G cells that secrete gastrin. The initial por­ tion of the stomach close to gastroesophageal junction Oxyntic Gland is called cardia. The proximal part of stomach is called the acid secreting oxyntic gland is typically a tubular and fundus, the middle and major part of stomach is the straight gland (Fig. It consists of neck, body and body or corpus, and the distal portion of the stomach is base. The oxyntic cells are present mainly in the body of the pylorus which contains pyloric sphincter: gland. Structure of a gastric gland containing chief cell and parietal cell is depicted in the inset. Structure of Oxyntic Cells Oxyntic cells or parietal cells are present in the body and neck of the oxyntic glands. On activation, the tubulovesicular membranes fuse with the cell membrane and microvilli that project into the canaliculi (Fig. Oxyntic or Parietal cells: Oxyntic cells are present Nerve Supply of Stomach mainly in the body part of the gland. Endocrine cells: the endocrine cells are also called tion inhibits gastric secretion and motility. G cells are present in antral the amount of gastric secretion per day varies from 1 to region that secrete gastrin. The dashed lines for K and Cl depict their passive diffusion into the gastric lumen. H –K pump actively pumps H (against its concentra­ mucin, rennin, gastric lipase, gelatinase, carbonic anhy­ tion gradient) out of the cell into the gastric lumen. This step can be blocked by − Type-I pepsinogen is found in chief cells in fundus acetazolamide, the carbonic anhydrase inhibitor. Consequently, following a meal that stimu­ lates gastric acid secretion, pH of blood increases. In the parietal cells, there are specific receptors Gastrin receptor; M : Muscarinic type 3 receptor; H : Histamine for these hormones and other hormones. Acetylcholine cell from basolateral membrane is also secreted into the Acetylcholine is an effective stimulator of gastric acid + lumen. It is released at the nerve endings of vagal cho- + + effective H ­K pump activity. Acetylcholine acts on the M3 cholinergic receptors on Secretion of Other Constituents ++ the parietal cells and increases intracellular Ca. Vagal fibers innervate G cells and vagal stimulation Mucus Secretion increases gastrin release. However, vagal fibers that Mucus is secreted by mucus secreting cells that are plen­ mediate gastrin release are non-cholinergic (Fig. Gastrin secretion from stomach is increased ble mucin, secreted from mainly cardiac and pyloric by gastric distension, noncholinergic vagal stimulation, mucosal cells. Mucin forms a protective layer on the gastric epithe­ used for assessing gastric acid output (Application Box lium. Histamine Neural factors – Vagal stimulation (cholinergic and noncholinergic) Blood borne – Epinephrine B. Factors that Inhibit Gastric Acid Secretion As G cells are present in antral part of stomach and gastrin is the strong stimulus for parietal cells, antrectomy (partial antral gastrectomy) is Increased acid output, somatostatin and acidic content of performed for surgical treatment for protracted peptic ulcer. Thus, histamine is considered as a major mediator of tion from D cells of stomach. Somatostatin inhibits secretion of gastrin from G cells are usually first treated with histamine type­2 recep­ that decreases acid secretion. Somatostatin Mechanical and Chemical Factors Somatostatin is secreted from the D cells of the gastric Accumulation of food in the stomach increases acid mucosa: secretion. Decreased pH of gastric content (pH less than 2) tension that stretches G cells and stimulates gastrin increases the secretion of somatostatin, which inhibits release. Secretin inhibits gastric secretion and motility, and gastrin release from G cells. There are other enterogastrones also that inhibit gas­ allowed to enter into the stomach, which is collected from neck tric secretion. Gastric juice is collected from the stomach through a cannula during the process of eating. Regulation of Gastric Secretion Gastric secretion is regulated by neural and humoral mecha­ stomach). The mechanism of regulation depends on the lected from the stomach by placing a cannula into it phase of gastric acid secretion. Then, bilateral vagotomy is performed and the gastric mechanisms regulating gastric secretion are discussed juice is collected following vagotomy for analysis. Vagotomy abolishes gastric secretion during cephalic Gastric secretion occurs in three phases (cephalic, phase, which proves that this phase is primarily vagally gastric and intestinal) and the mechanisms regulating mediated. Usually in parties and special dinners, sight, thought, taste and chewing of food. This is called enough time is spent initially in taking soup and appetizers before actual dinner is served. This is meant to stimulate appetite for food and to cephalic phase as impulses to increase acid secretion origi­ collect enough gastric juice in stomach before food enters the stomach, nate mainly in the brain: so that digestion becomes easier. Therefore, cephalic phase of Gastric Phase gastric secretion is entirely mediated by vagus nerve and the fibers are both cholinergic and noncholinergic the gastric phase of gastric secretion starts when food (see Fig. The primary stimulus for secretion in this phase is the cholinergic and fibers that contact G cells are noncho- distension of the stomach. As noncholinergic effects are stronger than choliner­ acids produced by pepsin action that breaks proteins gic effects, atropine can not effectively prevent vagally stimulate gastric secretion. The distension of the stomach elicits acid secretion by prescribed in the management of peptic ulcer. The the gastric juice secreted in the cephalic phase occurs central reflex is mediated by vagus nerve (vagovagal before food reaches the stomach. This phase accounts for 40–50% local reflex releases acetylcholine that directly stimu­ of total gastric secretion (Application Box 39.

Human sera are preferred for pas- sive immunization to avoid serum sickness induced by for- eign serum proteins levonorgestrel 0.18mg on line. Opsonic-promote ingestion and killing by phagocytic cells (IgG) Specifc immune response to extracellular bacteria: Block attachment (IgA) Antibodies are the primary agents that protect the body Neutralize toxins discount 0.18mg levonorgestrel otc. Microbial cell wall polysac- Agglutinate bacteria—may aid in clearing charides serve as thymus-independent antigens that stimulate Render motile organisms nonmotile specifc IgM antibody responses order levonorgestrel online pills. Cytokine production may Abs only rarely affect metabolism or growth of bacteria even permit switching from IgM to IgG production levonorgestrel 0.18 mg visa. When a bacterial toxin infammatory response and bringing fresh phagocytes stimulates an entire family of T lymphocytes that express and serum Abs into the site products of a certain family of vβT lymphocyte receptor Abs, combining with antigens of the bacterial surface, genes, it is referred to as a superantigen. Circulatory system infections: the principal infection Phagocytic cells are important antibacterial defenses. In acute endocarditis attribut- dependent and oxygen-independent antimicrobial mecha- able to Staphylococcus aureus, there is high fever and, if nisms. Oxygen-independent killing may be accomplished by untreated, a fatal rapid destruction of the heart valves. Cell-mediated subacute endocarditis there is a more indolent course and immunity mediated by T lymphocytes is another important immunologic complications follow. The principal causative microor- of lymphokines that have various types of consequences. Mechanisms of immunopathol- levels, measured by immunoblotting, are greatly increased ogy include septisemic shock in the adult respiratory distress in enterococcal or streptococcal endocarditis and these are syndrome; the Shwartzman reaction; the Koch phenomenon species specifc. Thus, the immune response to bacteria is varied and by all strains of this organism are identical immunologically, complex but effective in the animal organism with an intact which means that antitoxins may neutralize them equally. Immunization does not pro- An infection or bacterial allergy is a hypersensitivity, espe- tect against the infection but against the systemic and local cially of the delayed T cell type, that develops in subjects effects of the toxin. A high level of immunity is conferred but infected with certain microorganisms, such asMycobacterium it is not complete. Dapsone (diaminodiphenyl sulfone) is a sulfa drug that has Bacteriolysin is an agent such as an antibody or other sub- been used in the treatment of leprosy. Patients develop hemolysis, agranulocytosis, and hypoalbuminemia, as well as exfolia- Cat scratch disease or regional lymphadenitis, is common tive dermatitis and life-threatening hepatitis. Erythematous Encapsulated bacteria are surrounded by a thick carbohy- papules may appear on the hands or forearms at the site drate coating or capsule that protects microorganisms such of the injury. Infection-producing of the parotid gland, lymphadenapathy that is regional or encapsulated bacteria cannot be effectively phagocytized generalized, maculopapular rash, anorexia, splenic enlarge- and destroyed unless they are frst coated with an opsoniz- ment, and encephalopathy. There may be hyperplasia of ing antibody, formed in an adaptive immune response, and lymphoid tissues, formation of granulomas, and abscesses. Gentamycin and ciprofoxacin have been used in End-binders are selected anticarbohydrate-specifc anti- treatment. Chancre immunity describes the resistance to reinfection with Treponema pallidum that develops 3 months following the Fernandez reaction is an early (24 to 48-h) tubercu- a syphilis infection that is untreated. Cholera toxin is a Vibro cholerae enterotoxin comprised of fve B subunits that are cell-binding 11. Before combining the patient’s Jarisch-Herxheimer reaction is a systemic reaction associ- serum with killed T. It is apparently produced by the release of signif- ing, the specimen is covered with fuorescein-labeled antihu- cant quantities of toxic or antigenic substances from multiple man globulin. Demonstration of positive fuorescence of the target microorganisms reveals K antigens are surface epitopes of Gram-negative microor- specifc antibody present in the patient’s serum. They are labile to heat and cross-react with H antigens are epitopes on fagella of enteric bacteria that the capsules of other microorganisms such as Hemophilus are motile and Gram-negative. H is from the German word infuenzae, Streptococcus pneumoniae, and Neisseria men- hauch, which means breath, and refers to the production of ingitidis. K antigens may be linked to virulent strains of a flm on agar plates that resembles breathing on glass. Anti-K the Kaufmann–White classifcation scheme for Salmonella, antibodies are only weakly protective. Connecticut where an epidemic of juvenile rheumatoid Phase variation may result in a switch to production of the arthritis (Still’s disease) was found to be due to Borrelia other type that is genetically controlled. It is the most frequent zoonosis in the United States with concentration along the eastern coast. Insect Halogenation refers to halogen binding to the cell wall of a vectors include the deer tick (Ixodes dammini), white-footed microorganism with resulting injury to the microbe. Deer and feld mice Hib (Hemophilus infuenzae type b) is a microorganism are the hosts. In stage I, a rash termed erythema chroni- that induces infection mostly in infants less than 5 years of cum migrans occurs. Approximately 1000 deaths out of 20,000 annual cases papule and plaque that expands centrifugally to as much are recorded. This is accompanied by induration at the periph- only marginal effcacy and poorly immunogenic. The diagnosis requires the demonstration of IgG antibodies against the causative agent by Western Homozygote describes an organism whose genotype is immunoblotting. Lyme disease is treated with the anti- characterized by two identical alleles of a gene. Borrelia burgdorferi, the causative agent of this chronic infection, is Intimin is a bacterial membrane protein expressed on a spirochete that may evade the immune response. Mycoplasma immunity: High-titer cold agglutinin auto- antibodies against sialo-oligosaccharide of the Ii antigen type Intracellular pathogens are microorganisms, including are sometimes found during Mycoplasma pneumoniae infec- viruses and bacteria, that grow within cells. Yet mycoplasmas can survive neutrophil Extracellular pathogens are pathogenic microorganisms phagocytosis if specifc antibodies are not present. Secretory that reproduce in the interstitial fuid, blood or lumens of the IgA is signifcant in preventing localized colonization, yet respiratory, urogenital and gastrointestinal tracts rather than systemic antibodies protect from primary infection and sec- entering host cells. Mycoplasmas can evade the humoral immune response by undergoing anti- Invasive pathogens are pathogenic microorganisms that genic variation of surface antigens. T cells also appear to play successfully gains access to body even though defense mech- a role in immunity to mycoplasma, which needs to be further anisms are intact. It is antiphagocytic and facilitates viru- compared to the ratio of organism-specifc IgG in serum lence of streptococci. This is illustrated in the following formula: A protoplast is a bacterial cell from which the cell wall has been removed. It includes the cell protoplasm and the cyto- If the index is greater than 1, signifying a greater quantity plasmic membrane. The hypertonic solution protects them gests that the specifc organism of interest is producing an from lysis. Protoplasts can be produced from Gram-positive infection of the central nervous system. Similar indices can bacteria also by treatment with penicillin or other antibiot- be calculated for IgM and IgA antibody classes. Gram-negative bacteria have a cell wall comprised of a thin peptidoglycan A pathogen is an agent such as a microorganism that can layer enclosed by an exterior membrane of lipopolysaccha- produce disease through infection of the host. Protoplasts prepared from Gram-negative bacteria are frequently termed spheroplasts. They are natural or morphonuclear leukocytes infammatory responses leading to innate immune system receptors which recognize molecular the formation of pus at sites of infection. These receptors enhance natu- A pyogenic infection is infection associated with the gen- ral immune responses against microbes. Microorganisms that are well known for their macrophages that bind bacterial endotoxin to activate mac- pus-inducing or pyogenic potential include Streptococcal rophages, and the mannose receptor on phagocytes that bind pyogenes, Staphylococcus aureus, Streptococcus pneu- microbial glycoproteins or glycolipids, are examples of pattern moniae, and Hemophilus infuenzae. These plasma membrane or endocytic patients and those having defective phagocytic cell capac- vesicle membrane-bound pattern recognition molecules have ity show increased susceptibility to pyogenic infections. Pyogenic microorganisms stimulate a large polymorpho- Encapsulation is the reaction of leukocytes to foreign nuclear leukocyte response to their presence in tissues. Multiple layers of fattened leukocytes form a wall surround- Pyrogen is a substance that induces fever.

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Tese mechanisms are assigned to three The main rationale for surgical treatment in suitable cases is that major categories: (i) disease-related mechanisms buy generic levonorgestrel 0.18mg online, (ii) drug-related few interventions are as efective as brain surgery in this setting purchase 0.18mg levonorgestrel with visa, mechanisms discount levonorgestrel 0.18mg online, and (ii) pharmacogenetic mechanisms order generic levonorgestrel from india. Before discussing these mechanisms, we briefy con- drug-resistant epilepsy is valid only for the current and past drug sider whether ‘drug resistance’ is a worthy, unitary or even useful treatment. Finally, as discussed in this chapter, the concept of Morphological Drug-related factors drug-resistant epilepsy currently cannot ofer a unitary explanation (network) alterations (e. Drug response Interestingly, drug resistance has not only been observed in Drug efflux transporter Inflammatory processes alterations patients, but also in animal models of epilepsy [7]. Source: Adapted ing or with very poor response to monotherapy with at least two from Löscher et al. An alternative approach to develop animal models of the blood–brain barrier in epileptogenic brain regions due to ac- drug-resistant epilepsy is the treatment of a large group of kindled tivated efux transporters leads to drug resistance. An animal model of epilepsy allowing selection of subgroups of It is worthwhile noting that several mechanisms could act animals with drug-refractory and drug-responsive seizures could together and possibly even interact. It is almost certainly naïve to be a valuable tool to study why and how seizures become intractable think that only one mechanism explains drug resistance in an indi- and to develop more efective treatment strategies. In addition, assessing the clin- Two models that allow such subgroup selection have been devel- ical evidence for disease mechanisms of drug resistance is fraught oped and characterized by Löscher’s group [7]: the phenytoin-re- with a number of difculties. The concept of drug-resistant epilepsy, sistant kindled rat and the phenobarbital-resistant epileptic rat. By repeated testing of the antiseizure efect of phenytoin in large However, there is agreement that drug resistance is a graded pro- groups of fully kindled rats, we found that the individual response cess, and past treatment history does have some bearing on future of such rats to phenytoin difers; that is, that kindled seizures in response. Although relative drug resistance can be identifed afer some animals consistently respond and others never respond to failure of two past drugs [11], a signifcant minority of patients phenytoin [7]. For example, the use of carbamazepine in a patient with ab- nobarbital at maximal tolerated doses resulted in two subgroups: sence seizures and generalized spike–wave activity can exacerbate responders and non-responders [7]. Similarly, treating a patient with complex partial seizures phenobarbital non-responders, which was confrmed by several with ethosuximide is unlikely to be efcacious. When the as gabapentin, pregabalin, vigabatrin and lamotrigine can exacer- phenobarbital-resistant rats were subsequently treated with pheny- bate myoclonic seizures [1,14]. Plasma drug levels and adverse efects of [1,14], nor are mechanisms of comorbidity or mortality associated phenobarbital and phenytoin were comparable in responders and with drug resistance. Most of the poten- The underlying epilepsy syndrome is a signifcant predictor for tial mechanisms illustrated in Figure 7. Clinical features such as the epilepsy syndrome or the aeti- and a role for genetic factors (Figure 7. However, in some epileptic syndromes, the proportion of pa- tients with drug-resistant epilepsy varies considerably and the de- Disease-related mechanisms of drug terminants of this variation are largely unknown [1]. Schramm [28] noted that ly, similar observations were made in the rat model of basolateral class I evidence relating seizure outcome to the type and extent of amygdala stimulation that allows diferentiation of rats with difer- resection of mesial temporal lobe structures was inadequate. Epileptic rats that responded to treatment studies reviewed found no positive correlation between extent of exhibited a relatively low, uniform seizure frequency; none of the mesial resection and seizure-freedom afer surgery, and even leav- responders had a high seizure frequency. In contrast, many non-re- ing hippocampus and amygdala untouched could result in sei- sponders exhibited very high seizure frequencies. As in the structures of the mesial temporal lobe are involved in generating clinical situation [21], although high seizure frequency is a reliable or maintaining drug resistance is that the results of seizure free- predictor of pharmacoresistance [20], it is clearly not the only de- dom afer surgery can only be fully attributed to surgery if no pre- terminant of pharmacoresistance. Rogawski [19] mentioned other viously drug-resistant patients become seizure-free without surgery measures of epilepsy severity, such as the extent of structural lesions [27,29]. In a Furthermore, disease-related mechanisms of drug resistance study from Bonn, Germany, the seizure outcome of drug-resistant can change in the course of the epilepsy. Both groups seizure-free having relapsed and 10% had never been seizure-free received medical treatment. In a prospective, long-term, population-based study of 144 seizure-free in the last year of follow-up, as many as 24% of patients patients followed for a median of 40 years since their frst seizure became seizure-free without undergoing surgery, just with a change before the age of 16 years, 19% of patients were drug resistant from of medical regimen [31]. In addition, a number of clinical observa- the start to the end of follow-up, while a further 14% relapsed afer tions have reported that around 20% of formerly drug-resistant pa- remission and became drug resistant, indicating a worsening course tients with partial epilepsy, including patients ineligible for surgery, of epilepsy [22]. On the other hand, 32% of patients became sei- become seizure-free without surgery through a change of medical zure-free afer a median of 9 years of unsuccessful treatment and regimen [32,33,34]. Tese fndings have important implications in the search for This longitudinal study provided incontrovertible evidence that structural brain alterations associated with drug resistance. Tere is preliminary evidence from its underlying mechanisms must have changed over time. Seizures functional imaging [35,36] and from transcranial magnetic stimu- have been postulated to be, among other non-seizure-related fac- lation for changes in the contralateral hemisphere afer successful tors, involved in the generation of drug resistance. Extended changes in excitability and tion is supported by the observation that seizure clusters, defned in functional imaging afer surgery may be related to widespread as three or more seizures in 24 hours, occurring ofen as long as functional impairment in patients with partial epilepsy and sup- 15 years afer starting drug treatment, increased the risk of having port the existence of network changes beyond the resected area drug-resistant epilepsy by a factor of three compared with those in patients undergoing temporal lobe surgery. The network hypothesis of drug resistance afer surgery is based on the existence of non-resected limbic or extralimbic seizure-gen- Structural brain alterations and/or network changes erators lef behind during surgery. In experimental models of epilepsy tered in neocortical neurons from the same patients, and only half this has been called ‘rewiring the brain’ [42]. Indeed, loss of neurons in the hilus of the dentate gyrus, which macoresistant patients, whereas recovery was markedly slowed in is closely associated with development of granule cell disinhibition cells from carbamazepine-responsive patients [50]. The response to prolonged covery from inactivation of Na+ channels of hippocampal granule daily administration of phenobarbital at maximum tolerable doses neurons were signifcantly reduced, although not as pronounced as in epileptic rats of this model can be divided into two categories: a observed with carbamazepine, substantiating the concept that re- responder subgroup with control of seizures and a non-responder duced pharmacosensitivity of Na+ channels may contribute to the subgroup without any signifcant reduction in seizure frequency. This progressive development of pharmacore- correlated with profound alterations in receptor function and phar- sistance during a sustained status epilepticus is paralleled by alter- macology [57,58,59]. Tey found that: tumours, infectious diseases and several brain disorders[70,71,73]. Furthermore, P-gp is ex- sistant epileptic cases but not in drug-sensitive patients or postmor- pressed by tissues with excretory function (small intestine, liver and tem controls. Terefore the development of strategies for bypass- illary endothelial cells, astroglia and neurons following seizures (cf. This could explain that one of the major of inhibitors for the transporters has become an imperative for the predictors of drug resistance is high seizure frequency (or density) pharmaceutical industry [75]. Following the report by necessarily be restricted to the brain, but could also occur in other Tishler et al. If drug resistance is due to such processes, it should be pos- Mdr1 knockout mice were also used to demonstrate P-gp transport sible to demonstrate that the inhibition or avoidance of the of carbamazepine [85] and topiramate [86]. By using a rat microdi- resistance-mediating mechanism counteracts drug resistance in ep- alysis model with microdialysis probes in both brain hemispheres ilepsy. However, have an increased expression of P-gp in focal epileptiogenic brain subsequent data from our group demonstrated species diferenc- tissue. The only could be demonstrated with rodent but not human P-gp in an in exception was levetiracetam which was as efcacious in both re- vitro transport assay [87]. For this purpose, we used epileptic modify such assays in a way that allows evaluating active transport rats that were either responsive or resistant to phenobarbital [99]. A similar clinical tially identifed as substrates of human Pgp by our group, oxcarba- efect of verapamil was reported by Iannetti et al. However, zepine, eslicarbazepine acetate and the carbamazepine metabolite such anecdotes are weak evidence. Tus, clinical trials with more carbamazepine-10,11-epoxide are transported by human P-gp. One major reason for inconsistent data on this pol- develops to some drug efects much more rapidly than to others. Because of diverse confounding 2 have appropriate functionality; factors, detecting tolerance in patients with epilepsy is more dif- 3 be active in drug resistance (and not be an epiphenomenon); and cult but can be achieved with careful assessment of decline during 4 drug resistance should be afected when the mechanism is over- long-term individual patient response. We resistance in epilepsy did not include tolerance as a resistance mechanism in Table 7. For data on the hypotheses see the present and previous reviews [1,4,10,19,47,71]. New avenues for antiepileptic both mechanisms of refractoriness may coexist in the same epilep- drug discovery and development. N Engl J Med 2000; with epilepsy may be a consequence of the disease, the treatment, 342: 314–319. Quantifying the response to antiepileptic drugs: efect of past genetic factors or combinations of these possibilities. Long-term seizure outcomes following epi- pocampal sclerosis or cortical dysplasia) and beyond may be in- lepsy surgery: a systematic review and meta-analysis. Epi- severity and long-term progressive changes in neural networks dur- lepsy Behav 2008; 12: 501–539. Clinical aspects and biological bases of drug-resistant ep- ing development and progression of epilepsy may lead to reduced ilepsies. As outlined in this chapter, there are several other poten- and relapse in pediatric epilepsy: application of a Markov process.

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Antiisotype antibodies are synthesized in a dif- ferent species; antiallotype antibodies are made in the same Cμ is an immunoglobulin μ-chain constant region generic levonorgestrel 0.18 mg on line. The cor- species against allotypic variants; and antiidiotype antibod- responding exon is designated as Cμ purchase levonorgestrel 0.18mg with amex. Cγ is an immunoglobulin γ chain constant region that is fur- ther subdivided into four isotypes in man that are indicated Anti-immunoglobulin antibodies are produced by immu- as Cγ1 purchase genuine levonorgestrel on-line, Cγ2 purchase levonorgestrel 0.18mg with visa, Cγ3, and Cγ4. The corresponding exons are nizing one species with immunoglobulin antibodies derived expressed by the same designations in italics. Of the fve immunoglobu- lin classes in man, only the μ heavy chain of IgM and the ε Distribution ratio is the plasma immunoglobulin to whole heavy chain of IgE possess a fourth domain. Effector chains each contribute three hypervariable regions to the function generally results in removal of antigen from the antigen binding region of the antibody molecule. There is only minor variability in the amino acid con- region provides considerable fexibility to this area, which tent of constant domains. A globular compact structure that enables the Fab region of an immunoglobulin molecule to consists of two antiparallel twisted β sheets. There are differ- combine with cell surface epitopes that it might not otherwise ences in the number and the irregularity of the β strands and reach. Fab regions of an Ig molecule can rotate on the hinge bilayers in variable (V) and constant (C) subunits of immu- region. In addition to the proline resi- resembles that of the domains, which are comprised of a fve- dues, there may be one or several half cysteines associated strand β sheet and a four-strand β sheet packed facing one with the interchain disulfde bonds. However, the C domain does not have a hairpin loop or pepsin occurs near the hinge region. Thus, the C domain has seven chains each contain a hinge region, μ and ε chains do not. Constant region is that part of an immunoglobulin polypep- Homology unit: A structural feature of an immunoglobulin tide chain that has an invariant amino acid sequence among domain. A few exons encode are the areas for specifc antigen binding, and they also the constant region of an immunoglobulin heavy chain, and determine the idiotype of an immunoglobulin molecule. The one exon encodes the constant region of an immunoglobulin remaining background support structures of the heavy and light chain. It is associated the κ and λ light chain hot spots are situated near amino acid with a number of antibody functions. Digestion of IgG molecules with2 a particular specifcity without inducing an immune response papain yields two Fab and one Fc fragments. L chains have a single vari- able and constant domain, whereas H chains possess one A humanized antibody is an engineered antibody pro- variable and three to four constant domains. A human- is found in body secretions such as saliva, milk, and intes- ized antibody contains the antigen-binding specifcity of an tinal and bronchial secretions. IgD and IgM are present as antibody developed in a mouse, whereas the remainder of membrane-bound immunoglobulins on B cells, where they the molecule is of human origin. IgE, associated variable genes that encode the antigen-binding regions of a with anaphylaxis and IgG, which is the only immunoglobu- mouse antibody are transferred to the normal human gene lin capable of crossing the placenta, is the major human which encodes an immunoglobulin molecule that is mostly immunoglobulin. An immunoglobulin monomer is the basic unit of immu- noglobulin, comprised of two heavy chains and two light An immunoglobulin is a mature B cell product synthe- chains. Antibody molecules are immunoglobulins of defned specifcity pro- the homology region is a 105- to 115-amino acid residue duced by plasma cells. The immunoglobulin molecule con- sequence of heavy or light chains of immunoglobulins which sists of heavy (H) and light (L) chains fastened together have a primary structure that resembles other correspond- by disulfde bonds. A homology region has a classes and subclasses based on the antigenic specifcity globular shape and an intrachain disulfde bond. Heavy chains are designated by lower that encode homology regions are separated by introns. IgG, IgD, and IgE have two H Reagin (historical): (1) Obsolete term for a complement- and two L polypeptide chains, whereas IgM and IgA con- fxing IgM antibody reacting in the Wassermann test for sists of multimers of this basic chain structure. The basic monomeric unit is Y shaped, with a the Fcε receptors on tissue mast cells leading to release of hinge region rich in proline and susceptible to cleavage by histamine and vasoactive amines following interaction with proteolytic enzymes. Approximately 60% of human immunoglobulin antibody to the antibody heavy chain variable sequence. The fve immunoglobulin classes are termed isotypes They are smaller and less immunogenic than the intact based on the heavy-chain specifcity of each immuno- heavy chains with immunogenic constant regions. Two immunoglobulin classes, IgA and IgG, many possible uses are in imaging and treatment of cancer, have been further subdivided into subclasses based on H in cardiovascular disease, as biosensors, and for chemical chain differences. However, in certain disease states, and light chain variable regions fastened together by a fex- such as demyelinating diseases and infections of the central ible linker. This structure is present in membrane- sible to derive information about deviation from normal. Whereas tail peptides of 20 comparative method is called Ig quotient and is calculated in amino acids each are present in IgM and IgA molecules that various ways: have been secreted, IgG and IgE molecules do not contain tail peptides. Such antibodies patients with local immunoglobulin production show a may confer protective immunity. The heavy chain is comprised of three to four constant domains, depending on class, and one vari- Immunoglobulin function is to link an antigen to its able domain. In addition, a hinge region is present in some elimination mechanism (effector system). There is approximately 30% homology with respect complement activation and cellular elimination mechanisms to amino acid sequence among the fve classes of immuno- that include phagocytosis and antibody-dependent cell- globulin heavy chain in humans. This type of activation usually is μ, of IgG is γ, of IgA is α, of IgD is δ, and of IgE is ε. A requires antibody molecules clustered together on a cell heavy chain is a principal constituent of immunoglobulin surface rather than as free unliganded antibody. Antibodies can combine with virus particles to render them noninfectious in vitro through neutralization. All immunoglobulin classes can be expressed on B cell surfaces where they act as antigen Light chain receptors although this is mainly a function of IgM and IgD. Surface immunoglobulin has an extra C-terminal sequence compared to secreted immunoglobulin containing linker, transmembrane, and cytoplasmic segments. The amount present is dependent on the immunoglobulin concentration in the serum, the molecular size of the immunoglobulin, and the permeability of the blood–brain barrier. Each immunoglobulin is comprised of at least one four-polypeptide chain monomer which consists of two heavy and two light polypeptide chains. The two heavy L chain chains are identical in any one molecule as are the two light chains. A heavy chain is an immunoglobulin polypeptide chain that designates the class of immunoglobulin. The fve immunoglobulin classes are based on the heavy chains they possess and are IgM, IgG, IgA, IgD, and IgE. Heavy-chain antigenic determi- region or constant terminal reveals no variation except for nants determine not only the immunoglobulin class but the the Km and Oz allotype markers in humans. Heavy chain class refers to the immunoglobulin heavy polypeptide chain primary (antigenic) structure present κ chain is one of two types of light polypeptide chains in all members of a species that is different from the other present in immunoglobulin molecules of human and other heavy chain classes. Lowercase Greek letters such as μ, γ, α, δ, and ε in approximately 40% of human immunoglobulin molecules. A single immunoglobulin molecule contains either κ or λ light chains, not one of each. Each immunoglobulin is comprised of at Light chain type is a term for the classifcation of immu- least one four-polypeptide chain monomer, which consists of noglobulin light chains based on their primary or antigenic two heavy and two light polypeptide chains. Two types of light chains have been described and chains are identical in any one molecule as are the two light are designated as κ and λ. Heavy chain subclass: Within an immunoglobulin heavy chain class, differences in primary structure associated Kappa (κ) is the designation for one of the two types of with the constant region that can further distinguish these immunoglobulin light chain, with the other designated as heavy chains of the same class are designated as sub- lambda (λ). Heavy chain subclasses are designated as Lambda (λ) is one of the two light polypeptide chain types γ1, γ2, γ3, etc. Immunoglobulin heavy chain binding protein (BiP) is a Kappa-lambda exclusion is a means whereby the genera- 77-kDa protein that combines with selected membrane and tion of a functional κ light chain from the Igk locus on one secretory proteins. It is believed to facilitate their passage chromosome prevents further V(D)J rearrangement at the through the endoplasmic reticulum. Each four-chain Light chain subtype refers to the subdivision of a type of immunoglobulin monomer contains two identical light poly- light polypeptide chain based on its primary or antigenic peptide chains.

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Gestational age at diagnosis the ocular globe at the insertion of the optic nerve order 0.18mg levonorgestrel with visa. Note rocal showing proboscis (arrow) cheapest generic levonorgestrel uk, absent nasal bone order genuine levonorgestrel on-line, flat facial profile purchase levonorgestrel 0.18 mg otc, and bulging of posterior pole of globe (arrow). Prenatal magnetic resonance imaging of optic nerve head cyclopia and proboscis in a fetus with normal chromosome at 13 weeks coloboma. Reproduced with permission of gestation by three-dimensional transabdominal sonography. Associations included trisomy punctata type I,70 Micro syndrome,71 trisomy 13,12 trisomy 13, trisomy 18, trisomy 21, microcephaly without chromo­ 21,72and a supernumerary chromosome from chromosome somal anomaly, fetal alcohol syndrome, and fetal exposure 21P Four of the cases did not report outcome. The fetus Appearance on ultrasonography is of a conical echogenicity with Micro syndrome was born at term and was noted post- within the globe with the base at the lens and the apex natally to also have microphthalmia. In the remaining five towards the retina,62 and an increased thickness of the cases, cataract extraction was performed postnatally/’5*9-7176 hyaloid artery-lens junction (Fig. Walkcr-Warbjrg syndrome, cataracts Cataract’ 14-34 Hyperecnogemc lens Microphthalmia,*4v- hypertelorism and macroglobus,>: malformation of :he anterior segment and retinal dysplasia, and anophthalmia1- Mldhr. The characteristic feature on ultrasonography is a conical structure with its base towards the lens and its apex point­ ing posteriorly toward the optic nerve. Two were associ­ ated with Walker-Warburg syndrome, 4,79 and one was associated with Norrie disease. Prenatal two cases; one fetus with Walker-Warburg syndrome was ultrasonographic characteristic feature are a conical echogenicity within stillborn at 38 weeks,78 and the fetus with Norrie disease the globe, with the base at the lens and the apex towards the retina, had a normal term delivery. Primary hypertelorism results from undermigration of the paired nasal swellings, resulting in the two halves of the face lying too far apart. Secondary hypertelorism usually results from abnormalities of the skull, including anterior cephaloccle and craniosynostoses. Prenatal ultrasonographic characteristic feature is hyperechogenicity of the lens. Г,хг One fetus had showing bilateral echogenic lenses corresponding to fetal cataract. Prenatal ultrasonographic diagnosis Two outcomes were reported; the fetus with 13 q syndrome of persistent hyperplastic primary vitreous. The first was detected by ultrasonography at 21 halves of the face lying too close together. This usually weeks as an irregular, echogenic mass, surrounded by a results in an anomaly in the spectrum of holoproscnccphaly. The abnormalities of the bony skull, including microcephaly and second case was detected at 38 weeks; retinoblastoma plagiocephaly. Apert syndrome Orbttal cyst1* 23-27 Cystic orbital m ass - Rhabdomyosarcoma-"4 34 Irregular, echo-dense orbital m ass - Teratoma13 17 Solid and cystic m ass with complex - echogenicity Dacryocystocele11в*вт-вом-в* 27-38 Hypoechoic m ass inferomedial to Polyhydramnios. One case was associated with microphthalmia, hydrocepha­ lus, ventricular septal defect, pericardial effusion, and V omphalocele. The other >1 case was associated with an enlarged urinary bladder and choroid plexus dysmorphism. Prenatal ultrasonographic diagnosed at 23 weeks using transabdominal and trans­ characteristic features are increased inner and outer orbital distances (hypertelorism) and decreased inner and outer orbital diameters vaginal ultrasound. Singh reported a Hypoteiorism: Two. The differential diagnosis of prenatal + cataract, prenatal + retinoblastoma,prenatal + retinal dacryocystocele includes enccphaloccle, nasal glioma, detachment, prenatal + hypertelorism, prenatal + hypotelorism, rhabdyomyosarcoma, dermoid cyst, and hemangioma. Case reports published between January 1, 1980, A variety of ocular, orbital, and adnexal abnormalities have and September 15, 2009, were included. The indications tal ultrasonographic screening: impact on the detection, management, for intrauterine screening for globe, orbit, and adnexal and outcom e of anom alous fetuses. Further research is needed to determine screening and perinatal m ortality: controlled trial of system atic one- the value of screening and its effect on management and stage screening in pregnancy. First and the English medical literature and the world medical litera- second-trim ester diagnosis of fetal ocular defects and associated anomalies: report o f eight cases. Axial growth of the fetal eye and prenatal + anophthalmia, prenatal + microphthalmia, prenatal + evaluation of the hyaloid artery: in utero ultrasonographic study. A case report o f prcnatally holoprosencephaly and cyclopia with triploidy by transvaginal three- diagnosed ophthalm o-acrom elic syndrom e type W aardenburg. U ltrasound dom inant cataracts of the fetus: early detection by transvaginal O bstet G ynecol 2005;25:629-30. Л large retinoblastom a facial dcfccts, am niotic bands, adhesions and upper lim b deficiency. Congenital orbital cyst dctcctcd and m onitored by products o f conccption obtained by dilation an d evacuation. Prenatal detection of orbital trim ester diagnosis of cyclopia and holoprosencephaly. I Clin U ltrasound tom ography and m agnetic resonance im aging use during prcgnancy 1986;11:550-3. Philadelphia: trisom y 3p(3p23—> pter) an d m onosom y 7q(7q36— > qter) in a Lippincott W illiams & W ilkins, 2005. Prenatal diagnosis ofotocephaly proboscis in a fetus with norm al chrom osom e at 13 weeks o f gestation with m icrophthalm ia/anophthalm ia using ultrasound and magnetic by three-dim ensional transabdom inal sonography. C ongenital axial high m yopia detected by three-dim ensional ultrasound: a novel application of the reverse by prenatal ultrasound. Prenatal two- and three-dim ensional rhizomelic shortening and bilateral cataracts. Clinicopathological genital nasolacrim al duct cyst by ultrasonography: a case report. Traboulsi, and Ethylin Wang Jabs Syndromes with craniofacial malformations commonly be displaced or placed asymmetrically and there can be involve the orbits and arc sometimes associated with signifi­ hearing loss. It is beyond the scope of As the phenotypic expression of the craniosynostosis is this chapter to cover all the clinical details of the individual highly variable, the parents of an atfectcd child should syndromes and to include all syndromes with craniofacial always be examined for subtle abnormalities of cranial abnormalities. We will give a synopsis of the clinical features shape to rule out mild expression of the genetic condition. Craniosynostosis, or the premature fusion of one or more Molecular genetic testing is available and useful in olTering cranial sutures, occurs in approximately 1of 2,500 births and insights into the diagnosis, recurrence risk, prognosis, may lead to derangement of craniofacial development. Eighty-four children (and 61 relatives) had patho­ associated with abnormal development of any structure in logic genetic alterations (86% single-gene mutations and 14% the craniofacial region. More complex patterns of genetic syndromes have been described in which cranio­ plagiocephaly (asymmetric skull shape) are evident when synostosis is a feature. In syndromic cases, the most frequent synostosis is unilateral, or when there is a combination of concomitant anomalies involve the limbs, cars, and cardio­ sutures involved. The forehead may be prominent or receding, depend­ discs were pale or atrophic in 50% of Crouzon syndrome ing on the specific sutures involved. Disc swelling was and orbital involvement with hypertelorism, proptosis, stra­ present in 31% of Crouzon and 9. The midface is often depressed, which can lead to a with craniosynostotic syndromes looking for prevalence narrowed airway and respiratory difficulties. Causes of visual impairment included that occurs within and between the resulting syndromes. Risk factors for Jackson-Weiss syndrome cases are allelic and result from amblyopia were strabismus (43. In craniosynostotic syndromes,31 suggesting the effect of contrast, ocular findings in nonsyndromic craniosynostotic modifying genes elsewhere in the genome. These conditions have significant cephaly patients were studied, 7% had an exodeviation and variability in expression, and mild cases may go undiag­ 28% had astigmatism. Okajima and colleagues reported on nosed until the birth of an affected offspring with features three craniosynostosis patients with Ser35lCys mutation in characteristic of the individual clinical phenotype.

These preparations combine diph- theria and tetanus toxoids with acellular pertussis bacterial Pertussis vaccine (Figure 25 discount levonorgestrel 0.18mg overnight delivery. The acellular pertussis antigens include pertussis phylactic immunization against whooping cough in children cheap levonorgestrel 0.18 mg on line. Immunization with diphthe- It consists of virulent Bordetella pertussis microorganisms ria and tetanus toxoid is believed to confer protection lasting that have been killed by treatment with formalin generic levonorgestrel 0.18mg amex. Nevertheless cheap 0.18 mg levonorgestrel with amex, diphtheria toxoid does not prevent istered in conjunction with diphtheria toxoid and tetanus tox- carriage of Corynebacterium diphtheriae in the pharynx or oid as a so-called triple vaccine. Protection against pertussis lasts for 4 protective immunity against pertussis, the killed Bordetella to 6 years. Serum diphtheria and tetanus antitoxin levels of pertussis microorganisms act as an adjuvant and facilitate 0. Effcacy antibody production against the diphtheria and tetanus tox- of the pertussis component does not have a well-established oid components in vaccine. Triple vaccine is an immunizing preparation comprised of three components and used to protect infants against diph- Whooping cough vaccine: See pertussis vaccine. It is made up of diphtheria toxoid, pertussis vaccine, and tetanus tox- Diptheria and tetanus toxoids (adsorbed—injection) is oid. The second dose is administered 1 month cated for active immunization against diphtheria and tetanus later, and the third dose is given 6 months after the second. Results of the used in Europe as a vaccine against tuberculosis, although study indicated protective levels of antibody were raised in it never gained popularity in the United States. It has also more than 90% of the study population after primary immu- been used in tumor immunotherapy to nonspecifcally acti- nization with both components. Booster injections were vate the immune response in selected tumor-bearing patients, effective in 100% of individuals with pre-existing antibody such as those with melanoma or bladder cancer. It is claimed to protect against development of tuber- immunity against the disease, diminishing the risk of infec- culosis, although not all authorities agree on its effcacy for this tion by approximately 75%. It is intended for protection against tuberculosis in individuals not previously infected Typhus vaccine is an immunizing preparation that con- with Mycobacterium tuberculosis who are at high risk for tains killed rickettsiae microorganisms of a strain or strains exposure. It was designed for percutaneous use as an attenu- of epidemic typhus rickettsiae. Rickettsiae prepared in chick embryo Bacille Calmette-Guérin is an attenuated strain of yolk sacs or tissues are treated with formaldehyde to render Mycobacterium bovis that has been employed as a vaccine them inactive. This vaccine was more widely used in Europe Meningococcal vaccine is an immunizing preparation that than in the United States in an attempt to provide protection contains bacterial polysaccharides from certain types of against development of tuberculosis. C, Y, and W135 are available for preventing diseases induced serogroups A and C vaccines have clinical effcacies of by those serogroups. There is no vaccine for meningococcal 85–100% in older children and adults and are used to control serogroup B. Serogroups Y and W-135 polysaccharides are safe and immunogenic in adults and in children older than 2 years A meningococcal (groups A, C, Y, and W-135) polysac- of age. In the frst 3 years following a single dose of vaccine, charide diptheria toxoid conjugate vaccine uses bactericidal the measurable levels of antibodies against groups A and C anticapsular meningococcal antibodies that are associated polysaccharides decrease signifcantly. Meningococcal body occurs more rapidly in infants and younger children polysaccharide diphtheria toxoid conjugate vaccine induces than in adults. Vaccine-induced clinical protection probably synthesis of bactericidal antibodies specifc for the cap- persists in school children and adults for at least 3 years. Immunogenicity and clinical effcacy of serogroups A and Pneumococcal polysaccharide vaccine contains a polysac- C meningococcal vaccines have been well established. The charide found in the Streptococcus pneumoniae capsule that serogroup A polysaccharide induces antibody in children as is type specifc antigen. Serotypes of young as 3 months of age, although a response comparable this microorganism are based upon different specifcities in with that among adults is not achieved until 3 or 5 years of the capsular polysaccharide which is comprised of oligosac- age; the serogroup C component is weakly immunogenic in charide repeating units. Glucose and glucuronic acid are the recipients who are younger than 18–24 months of age. Vaccines and Immunization 783 Pneumococcal 7 valent conjugate vaccine is a pneumococ- cal vaccine employed to actively immunize infants and small children. The immunizing preparation is comprised of anti- gens derived from seven capsular serotypes of Streptococcus Carbohydrate Protein pneumoniae. It induces immunity for a duration of 3 bidity and mortality for a number of bacterial diseases in to 5 years. The vaccine is believed to protect against 90% of vulnerable populations such as the very young or adults with the pneumococcal types that induce serious illness in patients immunodefciencies. Children at high risk can be vaccinated at Haemophilus infuenzae 6 polysaccharide polyribosyl-ribitol- 6 months of age and reinoculated at 2 years of age. Vaccination against pneumococcal that induces infection mostly in infants less than 5 years of disease is of increasing signifcance as Streptococcus pneu- age. Approximately 1000 deaths out of 20,000 annual cases moniae becomes increasingly resistant to antibiotics. A polysaccharide vaccine (Hib Vac) was of only marginal effcacy and poorly immunogenic. By con- Pneumococcal vaccine polyvalent (injection) is for vacci- trast, anti-Hib vaccine, which contains capsular polysac- nation against pneumococcal disease caused by those pneu- charide of Hib bound covalently to a carrier protein such as mococcal types included in the vaccine. Protective capsular type- It diminishes the risks of epiglottitis, meningitis, and other specifc antibody usually appears by 3 weeks following H. Antibodies induced by bacterial capsular poly- saccharides are mainly by T cell-independent mechanisms. Haemophilus B conjugate vaccine is an injection used to Therefore, the response is generally poor in children younger induce protective antibody to Haemophilus b polysaccha- than 2 years of age whose immune systems have not yet ride. Data from a Finnish feld trial in children 18–71 months of age suggests that a titer of >1 mcg/ Conjugate vaccine (Figure 25. It induces B cell respon- to the saccharide in infants that primes for an anamnestic siveness against thymus-dependent antigens rather than to response and is mainly IgG. A second vaccine, comprised of nent booster response has been shown in children 12 months McEwen strain 45/20 killed microorganisms in a water-in- of age or older who previously received two or three doses. The high mutability of Plasmodium falciparum makes prospects for an effective vaccine dim. The vaccine is comprised of X-irradiated larvae to halt their development to adult forms. Schistosomiasis vaccines: Schistosomiasis (billharziasis), also termed snail fever, is the worst human disease induced by a metazoan parasite. Two isoforms of the schistosome X-irradiated enzyme glutathione-S-transferase have been investigated as candidates for a vaccine. Therapeutic Immunology 26 AntIoxIdAnts And ImmunIty reagents such as antibodies, T cells, or modifcations of them in therapy. Both types have been applied to animal models of Immune function depends on a balance between free radicals autoimmune diseases, and attempts are in progress to apply and the antioxidant status of the body. A prin- adults to high levels of oxidants leads to diminished immune cipal goal of immunotherapy is to selectively diminish the responses. Exposure to low levels of dietary antioxidants also unwanted immune response but retain protective immune decreases immune responses such as delayed type hyper- mechanisms. There is increased oxidative stress and immune induction of immunologic tolerance which is antigen-induced dysfunction in rheumatoid arthritis, aging, and cigarette specifc immunosuppression. Thus, Bystander suppression, nonspecifc immune suppression, supplemental antioxidants are useful in diminishing oxida- and antibody-dependent immunotherapy are other treatment tive stress and improving immune function. Therapeutic antisera are serum antibody preparations employed to either protect against disease or for disease ther- apy. They are distinct from antibody or antisera preparations ArgInIne And ImmunIty used for the serological identifcation of microorganisms. The dibasic nitrogen-rich amino acid arginine has a marked Therapeutic antisera, such as horse antitoxin against diph- immunomodulatory function. It is critical for the main- theria, were widely used earlier in the 20th century. A few tenance of nitrogen balance and physiologic functions in specifc antisera such as tetanus antitoxin are still used. Supplemental administration of arginine in experi- mental animals has led to increased thymic size, lymphocyte Tetanus antitoxin: Antibody raised by immunizing horses count, and a lymphocyte mitogenic response to mitogens against Clostridium tetani exotoxin. It protects to treat or prevent tetanus in individuals with contaminated against posttraumatic thymic involution and the impairment lesions. It enhances delayed hypersensitivity reac- tivity) may occur in individuals receiving second injections tions in animal studies and also promotes host antitumor because of sensitization to horse serum proteins following ini- responses. Arginine is essential for the function of various tial exposure to horse antitoxin.

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The second contains thrombin and calcium buy levonorgestrel 0.18 mg, of the patients who underwent collagen-fibrin glue treatment which acts as a cofactor cheapest levonorgestrel. The two components are maintained were healed compared to 54 % who received the collagen in separate syringes until a specially designed dual syringe implant alone order 0.18 mg levonorgestrel amex. Garcia-Olmo and colleagues [31] reported on applicator (Duploject® buy cheap levonorgestrel 0.18 mg line, Baxter Healthcare) (Fig. The fibrin clot begins to organize within seconds After a 1-year follow-up there was a 16 % success rate in of the two components mixing. As with autologous fibrin patients receiving fibrin glue alone compared to 71 % for glue the fibrin matrix contained within the clot also serves as patients who received fibrin glue in combination with scaffolding for tissue in-growth into the healing wound. Patients underwent surgical closure of the body’s native plasminogen system will destabilize the the internal opening and then were randomized to receive clot, and within 2 weeks, the entire synthetic clot is destabi- either stem cells alone, stem cells with fibrin glue, or fibrin lized and replaced by host tissues [19, 20 ]. Cintron approximately 40 % at 6 months were equivalent to fibrin glue alone and that when the three groups were compared no statistically significant differences were found. The utiliza- tion of fibrin sealant for these applications is still in its infancy and continues to evolve. The reasons for this are multiple, including high fibrinogen concentrations with commercially prepared prod- ucts, uniform production, advanced viral inactivation tech- niques, easy and quick preparation, no need for patient blood donation, greater quantities easily available, and consistent high bonding power. Preoperative mechanical bowel preparation is not required, other than an enema on the morn- ing of surgery to evacuate the distal rectum. Patient positioning is at the discretion of the surgeon, pro- With permission © Micromedics Inc. Location of the primary or internal opening is essential in order to improve the success of the procedure. Occasionally hydrogen peroxide is utilized in order to inject the fistula tract in order to locate the primary opening. Either an unfolded gauze sponge, a silk suture with a series of knots, a small curette, or a cytology brush works well (Fig. Aggressive curettage or debridement should be avoided so as not to dilate the fistula tract. Dilation of the tract can lead to a greater quantity of sealant required to fill the fistula and to a higher risk of fibrin clot extrusion from the tract. After debridement the tract should be irri- gated with saline or hydrogen peroxide to further cleanse the tract. Iodine irrigation of the tract should be avoided because iodine solutions can destabilize the fibrin clot. A dual syringe applicator and dual lumen catheter is utilized containing the two components, which will mix together at the tip when injected. Other delivery systems are available including malleable dual lumen catheters (Fig. The catheter tip is first placed into the external orifice, through the tract, tract initially, which can then be secured to the catheter. This is the tie is then used to drag the dual lumen catheter with it usually accomplished by placing a tie/seton through the and into the tract towards the primary opening (Fig. Anaphylactic reac- primary opening, the catheter is slowly withdrawn through the tions to the antifibrinolytic protein aprotinin have been tract as sealant is being injected, thus obliterating the entire reported especially in patients who have had prior exposure tract (Fig. The external orifice is then dressed with a non-adherent the risk that the plasma may contain infectious agents such dressing. Patients are discharged home on the day of surgery, as known viruses (parvovirus), emerging viruses, or other as there is minimal or no postoperative pain. Complete obliteration of the tract and any of its side regarding excessive bleeding following the use of bovine branches with sealant is the critical feature of the procedure. If an abscess is identified at the time of examination, it should Some patients have been reported to develop acquired coag- be drained and a seton placed, and fibrin gluing deferred for ulation factor inhibitors in response to bovine thrombin a later date. This does not seem to be the case when patients are reexposed to recombinant human thrombin which is uti- lized with greater frequency today [36]. The antibodies to Complications Associated bovine Factor V have been shown to elicit cross-reactivity with Fibrin Sealant with human Factor V, which potentially can decrease the amount of Factor V available, with subsequent inhibition of One of the most common complications associated with the the clotting cascade [37]. This reaction is minimized via use of fibrin sealant for anorectal fistulas is the development lower thrombin concentrations and through the use of Factor of infection typically at the site of the external or secondary V-depleted bovine thrombin preparations [38]. It is important not to suture close the secondary opening at the time of gluing as this can lead to an increased Literature Review incidence of infection. Other complications or side effects may be secondary to the components that constitute the Over the past one and a half decades there have been an product itself. As previously described, it is critical to obliterate methodology of reported studies makes comparison difficult. For this Few trials were initially prospective and randomized [39, 40 ], reason, some authors chose to exclude patients in whom some were prospective and nonrandomized [23, 27 , 41 – 48 ], additional tracts were identified [27, 39 , 43, 46] or deferred while others were retrospective [49, 50]. The patients the injection until adequate drainage was achieved [25 , 40 , included in the majority of the trials were usually not stan- 41 , 48 , 49 , 51]. Preoperative antibiotic use was also tive patients, rectovaginal fistulae, and anastomotic fistulae. Authors administered paren- the commercial preparations of sealant are varied, and the teral antibiotics [23, 43 , 47], enteral antibiotics [44], or intraoperative protocols differ in terms of preoperative prep- refrained from antibiotic use [39 , 41]. There is evidence to aration of the patient, management of the fistula in the oper- suggest that antibiotics mixed within the fibrin sealant ating room, and postoperative monitoring. Because of the variability in design, a formal remaining patients having postoperative persistent perineal systematic review or meta-analysis, although attempted, has sinuses. Although this series was small, it provided the first not really provided useful information. Nonetheless, a review available data suggesting safety and efficacy for anal fistulas. Additionally, They reported a 60 % success with a mixed group of patients on occasion statistics may differ slightly as I thought it would that included five patients who had rectovaginal fistulae, be appropriate to not always dismiss patients who were lost to four of whom were successfully treated. Ramanujam [47] reported results from 30 patients, all of In 1991 Hjortrup and colleagues [27] in Europe described whom had recurrent fistulae from various etiologies utilizing the first cohort of patients successfully treated with a autologous fibrin glue. With a follow-up range from 9 to 11 Fibrin Sealant 77 57 months their overall success was 60 % in this complicated commercial sealant was used to treat anal fistulae. This was group, despite the variety of diagnoses and previous treat- the first randomized controlled trial published involving ment failures. They compared fibrin glue using commercial sealant with cryptoglandular fistulas over with conventional surgical treatments. They reported zero success over the vaginal fistulas or fistulas with side branches were excluded. The fistulas were of various egy of reinjection brought initial healing rates of 42 % up to etiologies and the fibrin adhesive was a third-generation 63 % overall. This confirmed that retreatment is a reasonable autologous glue prepared via ethanol precipitation. Although option in patients failing their initial injection, although reporting an 85 % success rate, follow-up was short at only follow-up was short in their study. They subsequently published their long-term sealant to be more efficacious in patients with complex fistu- follow-up in a mixed cohort of patients utilizing autologous las compared to simple fistulas. They included ten patients in their study and and 53 patients were treated with commercial sealant. El-Bakry [54] reported their results in 19 patients with a total Nelson and colleagues [7] published their results looking at of 21 fistulae from the Kingdom of Saudi Arabia. From their patients were lost to follow-up and 14 out of 18 had that group commercial fibrin sealant was used in conjunction successful closure for an overall healing of 78 % with 1-year with a dermal island-flap anoplasty in ten patients with trans- follow-up. The anal fistulas were of cryptoglandular their experience with complex fistulae (high transsphinc- etiology and they reported a 50 % success rate over a teric, suprasphincteric, high rectovaginal, and Crohn’s fistu- 28-month follow-up on those patients who underwent con- lae) in 37 patients. Of note, there was a higher rate; however, when combined with a simultaneous endorec- failure rate when fibrin sealant was used in conjunction with tal advancement flap, healing was 54 %. Although subsequently presented a prospective multicenter study numbers were small, simultaneous use of fibrin glue was not enrolling 60 patients [51]. Additionally, study in which anal fistulae were treated with sealant that the thrombin concentration was significantly enhanced. Overall healing was 74 % and there was tive trial with commercial fibrin sealant in conjunction with greater efficacy in patients whose fistula tract was ≥3. This was the first study suggesting that intra-adhesive ing over a median 14-month follow-up. Despite the [45] presented at the Association of Coloproctology of Great presence of healing of the secondary skin opening in 77 % of Britain and Ireland their results with a series of 30 patients patients at 2 weeks, only 14 % remained healed at 16-month utilizing autologous fibrin glue in fistulas of cryptoglandular follow-up.

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