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Even the journal entitled Immunochemistry was gation that 19S antibody is found early and 7S antibody late renamed Molecular Immunology order kamagra 50mg with visa. In 1959 kamagra 50mg otc, Rodney Porter working in England demonstrated that antibody molecules could be split Jan Gosta Waldenström (1906–1996) cheap kamagra line, Swedish physician into fragments by the enzyme papain proven kamagra 100 mg. He found that those who described macroglobulinemia, which now bears his fragments which remained in the supernatant of his reac- name. He subsequently designated these of immunochemistry, was born on April 29, 1888, in New as Fab and Fc fragments (i. Following completion of his PhD in organic and fragment crystallizable, respectively). In 1969, Gerald chemistry at Columbia and postdoctoral training with Edelman reported the results of his primary sequence analy- Richard Willstätter in Zurich, he returned to a position at the sis of a human myeloma protein (namely immunoglobulin G, Rockefeller Institute for Medical Research in New York City. The isolation of suffcient homogeneous antibody from He and Jacobs discovered tryparsamide, which proved very the serum of a patient with multiple myeloma over a signif- effective in the treatment of African sleeping sickness. In Van cant period of time had overcome the previous diffculty of Slyke’s laboratory at the Rockefeller Institute, he perfected the attempting to analyze heterogeneous antibodies. History of Immunology 23 This brought him into contact with Karl Landsteiner, with whom he published two classic articles comparing immuno- logic and solubility techniques for distinguishing hemoglo- bins of different species. Avery requested his assistance with the biochemical analysis of “specifc soluble substance” of pneumococci. He purifed Avery’s broth con- centrate until the components were free of nitrogen, showing that it was indeed specifc soluble substance. He precipitated the preparation with antiserum and recovered the same poly- saccharide. This led to extensive future investigations by Heidelberger, Goebel, Avery, and others on the specifcity of naturally occurring antigens. Precipitin analyses permitted estimation of the quantities of numerous antigens in native materials without the need for tedious isolation and purif- cation. Heidelberger accepted an appointment as associate professor of medicine at Columbia Physicians and Surgeons, where he and Kendall developed a quantitative theory defn- ing the precipitin reaction of polysaccharides. Together with Kabat and Kendall, he demonstrated that antibodies were globulins and that specifc precipitation, agglutination, and figure 1. They also performed classic experiments proving of immunoglobulin chain variable regions. He received the complement to be a real nitrogen-containing substance, or National Medal of Science. He twice served chemist who was educated at the University of Uppsala, as president of the American Association of Immunologists in where he also worked in research. Among his many honors are the Lasker, Behring, Institute for Advanced Study in Princeton. Awarded the Légion d’honneur and the Académie de Médecine of France, Nobel Prize in Chemistry in 1948, he perfected the electro- and the National Medal of Science, as well as a spate of hon- phoresis technique and classifed antibodies as K globulins orary degrees from the world’s leading universities. After 27 years at Columbia Physicians and Surgeons, at 67 years of age, he accepted Dr. Selman Waksman’s invitation to join the Institute of Microbiology at Rutgers where, for nearly a decade, he inspired the Immunochemistry Group to pursue novel and innovative research. Upon leaving Rutgers, at the age of 76, Professor Heidelberger continued his research in the Department of Pathology at New York University. He began a series of challenging investigations on cross-reactivity of microorganisms and of plant polysaccharides, publishing many papers on immunologic relationships among their structures. Professor Heidelberger’s life work was aimed at the development of rigorous quantitative techniques for purifcation of antibody molecules and investigations on the specifcity of naturally occurring antigens. Other contributions include research on antibodies to carbohydrates, the antibody combining site, and the discovery figure 1. Herman Nathaniel Eisen (1918– ), American physician whose research contributions range from equilibrium dialy- figure 1. He also developed synthetic investigator who was professor at the Rockefeller University blood plasmas. Edelman was the frst to demonstrate John Richardson Marrack (1899–1976) (Figure 1. He also did pioneering work with Bence pathology at Cambridge and at the London Hospital. He Jones protein, cell adhesion molecules, immunoglobulin hypothesized that antibodies are bivalent, labeled anti- amino acid sequence, and neurobiology. Porter cleaved antibody molecules with the enzyme papain to yield Fab and Fc fragments. Fab frag- ments were shown to have the antigen-binding sites, whereas the Fc fragment conferred the antibody’s biological proper- ties. A ferment of research activity in the latter 1800s was designed to elucidate mechanisms of host immunity against infectious disease agents. Elie Metchnikoff’s demonstration that blood cells could phagocy- tize (ingest) invading microorganisms led to the cellular the- ory, the frst of two opposing concepts of bacteriolysis. Buchner’s detection of the heat-labile constituent of fresh, History of Immunology 25 cell-free serum, which could include bacteriolysis. In 1889, Buchner described a heat-labile bactericidal principle in the blood, which he termed alexine. In 1894, Pfeiffer discovered specifc in vivo lysis of bacteria by observing that cholera vibrios injected into the peritoneum of immune guinea pigs were lysed. In 1895, Jules Bordet, working at the Institut Pasteur in Metchnikoff’s laboratory, extended this fnding by demonstrating that the lytic or bactericidal action of freshly drawn blood, which had been destroyed by heating, was promptly restored by the addition of fresh, nor- mal, unheated serum. In 1901, Bordet and Gengou developed the complement fxation test to measure antigen–antibody reac- tions. Through his studies of normal serum and its bactericidal effects, he became an advocate of director of the Rabies and Bacteriology Institute of Brabant the humoral theory of immunity. He received Madame Marie Pasteur’s permis- sion to rename the facility the Institut Pasteur de Bruxelles Jules Jean Baptiste Vincent Bordet (1870–1961) in 1903. In addition to his discovery of Bordetella pertus- whooping cough, immune hemolysis, and complement fxa- sis, Bordet also described the mycoplasma of bovine pleu- tion. He received the Nobel Prize in Medicine or Physiology ropneumonia, bacteriophage lysogeny. These Soignies, Belgium, and at age 16 entered the University of are in addition to his legion of discoveries in immunology Brussels, graduating as doctor of medicine in 1892. By 1890, that include specifc agglutination (1895), conglutination Jules was enhancing the virulence of Vibrio metschnikovii (1909), the antigenicity of antibodies and complement and, by passage in immunized animals. Richard Pfeiffer to the phenomenon of hemolysis described In 1897 he traveled to the Transvaal to investigate rinder- by Hans Buchner, Bordet decided to use the red blood cell pest. He left the Institut Pasteur in 1901 to accept the post as system to illustrate complement activity rather than lysis of pathogenic bacteria as a model system. The lytic action of serum was sensitive to heat but could be restored by the addition of unheated normal serum. Bordet’s experi- ment showed complement to be nonspecifc and able to function only when target cells were sensitized. In 1900, Bordet showed that complement action was nonspecifc by using the same source of complement for both hemolysis and bacterial lysis. He and Gengou described complement fxation, and pointed to its use in the diagnosis of infec- tious diseases. They showed that complement, specifcally C1, is fxed by bacteria that resist lysis, providing the foun- dation for the highly sensitive complement fxation test to detect specifc antibodies in serum. Von Wassermann applied the complement fxation technique to the diagno- sis of syphilis, which was used worldwide. For example, Bordet believed toxin to 26 Atlas of Immunology, Third Edition be neutralized by antitoxin through adsorption, similar to a the classical pathway of complement activation was described fabric interacting with a dye. He considered antitoxic sera frst by investigators using sheep red blood cells sensitized to contain substance sensibilisatrice (i. He postulated that this acts component and postulated an alternative pathway of comple- as a mordant does for a dyestuff.

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The genesis in cells linked to migratory patterns of hematopoietic stem cell compartment is composed of a continuum of cells stem cells order cheap kamagra on line, melanoblasts kamagra 100 mg overnight delivery, and germ cells purchase genuine kamagra on line. They may be altered genetically in vitro precursor cells that are multipotential with the capacity to and introduced into mouse blastocysts to give rise to mutant yield differentiated cell types with different functions and murine lines buy kamagra 50mg without prescription. Pluripotency: the versatility to differentiate into one of An erythroid progenitor is an immature cell that leads to various types of cells. A pluripotent stem cell is a continuously dividing, undif- ferentiated bone marrow cell that has progeny consisting of Erythropoiesis refers to the formation of erythrocytes or additional stem cells together with cells of multiple separate red blood cells. Bone marrow hematopoietic stem cells may develop into cells of the myeloid, lymphoid, and erythroid lineages. Erythropoietin is a 46-kDa glycoprotein produced by the kidney, more specifcally by cells adjacent to the proximal Differentiation istheprocesswherebydevelopingaprecursor renal tubules, based on the presence of substances such as cell or an activated cell achieves functional specialization. It is useful (end-stage) hematopoietic cells in the blood are considered to in the treatment of various types of anemia. Some progenitor cells are precursors of erythrocytes, others are precursors of polymorphonuclear Hematopoiesis is the development of the cellular elements leukocytes and monocytes, and still others are megakaryo- of the blood including erythrocytes, leukocytes, and plate- cyte and platelet precursors. A gauge of the number of lets from pluripotent stem cells in the bone marrow in fetal hematopoietic progenitors in a specimen capable of forming liver. It is regulated by various cytokine growth factors syn- a colony comprised of a specifc type or types of hematopoi- thesized by bone marrow stromal cells, T cells, or other types etic cells. An A hematopoietic cell is a term referring to both an erythro- inducible endothelial–leukocyte adhesion molecule that pro- cyte and a leukocyte. Surface adherent leukocytes undergo a large A hemocytoblast is a bone marrow stem cell. Both Ca2+ and protein kinase C play a undifferentiated and serves as a precursor for multiple cell key role in the activation pathway. It is a common pluripotent hematopoietic precur- ity of phagocytes to bind and ingest opsonized particles. These cells are also demonstrable in the yolk sac Leukocyte adhesion molecules are facilitators of vascular and later in the liver in the fetus. The three main families of leukocyte adhesion mol- lead to the formation of granulocytes, monocytes, and ecules include the selectins, integrins, and immunoglobulin macrophages. These defciencies prevent granulocytes cells from which all lymphocytes are derived. Pluripotent from migrating to extravascular sites of infammation, lead- hematopoietic stem cells give rise to these progenitors. It consists of at least fve high molecular weight glycopro- teins present on the surface of the majority of human leuko- A myeloblast is a myeloid lineage immature hematopoietic cytes (mol wts: 180, 190, 205, and 220 kDa). The variation between the isoforms is all in the of granulocyte precursors and possesses nongranular baso- extracellular region. The principal types of tyrosine phosphatase that is expressed in various isoforms leukocytes in the peripheral blood of man include polymor- on different types of cells, including the different subtypes phonuclear neutrophils, eosinophils and basophils (granulo- of T cells. Leukopenia is the reduction below normal of the number of white blood cells in the peripheral blood. Leukocyte adhesion molecule-1 is a homing protein found on membranes, which combines with target cell specifc gly- coconjugates. It helps to regulate migration of leukocytes A progenitor cell no longer contains the capacity for self- through lymphocytes binding to high endothelial venules and renewal and is committed to the generation of a specifc cell to regulate neutrophil adherence to endothelium at infam- lineage. A lymphoid progenitor cell is a cell belonging to the lym- Leukocyte adhesion proteins are membrane-associated phoid lineage, such as a bone marrow stem cell, that gives dimeric glycoproteins comprised of a unique α subunit and a rise to all lymphocytes. They form frequently following antigenic or mito- regulation of infammatory responses of both immune and genic challenge of lymphoid cells, which leads to enlargement nonimmune origin. The chromatin is densely packed and Mononuclear cells are leukocytes with single, round nuclei stains dark blue with Romanowsky stains. Small lympho- such as lymphocytes and macrophages, in contrast to poly- cytes contain a thin rim of robin’s egg blue cytoplasm; a few morphonuclear leukocytes. Lymphocytes Lymphoid cell series (1) Cell lineages whose members mor- are divided into two principal groups termed B and T lym- phologically resemble lymphocytes, their progenitors, and phocytes, which can be distinguished phenotypically by their their progeny. These include the lymph nodes, thymus, sion of distinctive surface molecules that have precise roles spleen, and gut-associated lymphoid tissue, among others. In addition, natural killer cells, which are large granular lymphocytes, comprise a small percentage Lymphopenia is a decrease below normal in the number of of the lymphocyte population. Lymphopoiesis is the differentiation of hematopoietic stem Lymphocyte specifcity is the restricted and unique epitopes cells into common lymphoid progenitors and ultimately into a lymphocyte may be able to bind based on its expression of lymphocytes. Lymphoreticular is an adjective describing the system A lymphoid cell is a cell of the lymphoid system. The clas- composed of lymphocytes and monocyte-macrophages, as sic lymphoid cell is the lymphocyte. Molecules, Cells, and Tissues of the Immune Response 103 A long-lived lymphocyte is a small lymphocyte derived principally from the thymus that survives for months to years without dividing. An effector lymphocyte is a lymphocyte activated through either specifc or nonspecifc mechanisms to carry out a cer- tain function in the immune response. They are differentiated descendants of an activated leukocyte that remove a non-self- constituent. Most commonly, the term signifes a T lym- In Wright’s and Giemsa-stained blood smears, the nucleus phocyte capable of mediating cytotoxicity, suppression, or stains dark blue and is encircled by a narrow rim of robin’s helper function. Even though most of the lymphocytes look alike, they differ greatly in origin and function. They A nonadherent cell is a cell that fails to stick to a surface differ in other features as well. A lymphocyte is an example of a non- and B lymphocytes and the E rosette subpopulations look adherent cell, whereas macrophages readily adhere to the the same. However, they have different phenotypic sur- glass surface of a tissue culture fask. This is a com- mon designation for resting T and B lymphocytes that are Paracortex is a T lymphocyte thymus-dependent area recirculating. An activated lymphocyte is a lymphocyte whose cell sur- face receptors have interacted with a specifc antigen or with a mitogen such as phytohemagglutinin, concanavalin A, or staphylococcal protein A. The morphologic appear- ance of activated (or stimulated) lymphocytes is character- istic, and in this form the cells are called immunoblasts. The cells increase in size from 15 to 30 mm in diameter; show increased cytoplasmic basophilia; and develop vacuoles, lysosomes, and ribosomal aggregates. The nucleus contains very little chromatin, which is limited to a thin marginal layer, and the nucleolus becomes conspicuous. An activated B lymphocyte may synthesize antibody molecules, whereas an activated T cell may mediate a cellular immune reaction. By light microscopy, resting lymphocytes appear as a dis- tinct and homogeneous population of round cells, each with figure 2. The small lymphocyte variant, which is the predominant morphologic form, is slightly larger than Lymphocyte traffcking is a process that is critical for an erythrocyte. Larger lymphocytes, ranging between 10 interaction of the lymphocyte surface antigen receptor with and 20 μm in diameter, are diffcult to differentiate from epitopes. They have more cytoplasm and may show azuro- the blood into lymphoid and nonlymphoid organs and back philic granules. Intermediate-size forms between the two again to the blood by way of the lymphatics and venules. By phase contrast microscopy, living lym- Lymphocytes remain in the blood circulation for approxi- phocytes show a feeble motility with ameboid movements mately 30 min on each passage. The mirror handle circulation are exchanged approximately 48 times per day, is called a uropod. In large lymphocytes, mitochondria and about 5 × 1011 lymphocytes leave the blood circulation and lysosomes are better visualized, and some cells show each day. The tent lymphocytes specifc for each antigen, lymphocyte traf- different classes of lymphocytes cannot be distinguished by fcking increases the probability of interaction between the light microscopy. By scanning electron microscopy, B lym- lymphocyte and the epitope for which it is specifc. Several phocytes sometimes show a hairy (rough) surface, but this is adhesion molecules participate in receptor–ligand interac- apparently an artifact. Electron microscopy does not provide tions involved in the entry of lymphocytes into lymphoid additional information except for visualization of the cel- organs through endothelial venules. However, under appropriate stimulation, they are capable of consider- Lymphocyte recirculation is the process of lymphocyte able morphologic changes.

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Impact of presurgical psychiatric illness on postsurgical seizure outcome It is counterintuitive to associate a presurgical psychiatric history Impact of presurgical psychiatric history with a postsurgical seizure outcome buy kamagra 50mg fast delivery. Likewise order 100mg kamagra free shipping, Kanner cortex and the identifcation of patients at risk for postsurgical cog- et al cheap 50 mg kamagra free shipping. Unfortunately discount kamagra 100 mg without prescription, this is not always the others by the shorter postsurgical follow-up period, which may ac- case. A review of the literature identifed the following variables as count for the diferences. Tey found included working before surgery, achieving a seizure-free state, that preoperative anxiety disorders and personality disorders were a negative lifetime history of depression and female gender [59]. Of note, there was no diference among centres in which the same Tese data raise the question: Is it possible that a psychiatric his- (30%) or diferent (33%) psychiatrists performed the evaluation. The explanations for this phenomenon remain unknown chiatric aspects of epilepsy are more ‘attuned’ to potential postsur- at this time. Yet, several theories have been postulated by this au- gical psychiatric complications. Tese data also raise the question thor [66,67] but their review is beyond the scope of this chapter. In fact, 35 centres (75%) voiced concerns on the failure to Psychiatric aspects of paediatric epilepsy obtain in-depth psychiatric evaluations. In of pervasive developmental disorder, which was not present post- contrast, only 4 out of the 12 centres (33%) with an epilepsy team surgically in two of 23 patients who were diagnosed with this con- psychiatrist relied on these criteria. Afer all, most neuropsychological eval- the majority of which (73%) consisted of frontal resections [69]. As uations rely on screening instruments aimed at identifying current in temporal resections, there was no signifcant change in psychiat- psychiatric symptoms occurring during the prior 1–4 weeks, de- ric diagnosis before (44%) and afer surgery (45%). Clearly, psychi- pending on the instrument used; thus, these instruments are likely atric aspects of respective epilepsy surgery in children remain an to fail to detect any past psychiatric history that may be in remission unexplored area. Indeed, only Presurgical psychiatric protocols with a comprehensive psychiatric evaluation that investigates pres- ent and lifetime histories can clinicians have the necessary infor- the obstacles to perform presurgical psychiatric mation to formulate a correct psychiatric diagnosis, recommend evaluation the appropriate treatment and make estimations on the risk for po- The data presented in this chapter indicates the relatively high prev- tential postsurgical psychiatric complications. In the survey of 47 major epilepsy centres in North America neuropsychological evaluation. In short, screening instruments do cited in the introduction of this chapter, one question asked wheth- not identify the complexity of such psychiatric comorbidities. Can epileptologists and neuropsychologists rely on a The data indicated the absence of a consensus on this issue, as 21 patient’s self-report of past or concurrent psychiatric centres (45%) considered it to be a problem and 26 (55%) did not. Data from the survey revealed that only 10 centres (21%) rou- The answer to this question is also ‘no’! Terefore, the survey enquired on these disorders are reported by the patients to the physicians [70]. Among the In addition, some patients may not volunteer information on a co- 47 centres, only 12 (26%) had a psychiatrist in their epilepsy team. Failure to recognize whereas in 24 (51%) consultations were carried out by diferent psy- chronic depressive disorders is illustrated in a study of 97 patients chiatrists. In one centre, consultations were done by the residents with focal epilepsy with a depressive disorder severe enough to war- but the attending did not see the patients in person. Only one-third of the 97 patients had been treated within gical psychiatric complications. Tus, epilepsy centres that wish to have a psychiatrist in and validated in many languages and non-physicians can be trained their team will have to budget a fraction of the psychiatrist’s salary to administer this instrument. Indeed, depending on the question being addressed Suggested protocols by the specifc study, special sections of a questionnaire can be ad- Clearly, the evidence presented in the previous sections suggests ministered. For example, in the case of a study on mood and anxi- that patients who undergo epilepsy surgery are at risk for postsurgi- ety disorders, investigators can decide to administer the section of cal psychiatric complications. Accordingly, presurgical psychiatric these disorders of the chosen structured interview. We cannot emphasize enough the need to include an instru- • a detailed history of the temporal relationship of psychiatric ment that investigates the family psychiatric history. Indeed, psychiatric disorders • an assessment of family dynamics and, specifcally, the role played are associated with neuroanatomical, neuropathological and neuro- by each spouse with respect to the decision-making process in chemical changes that develop over time [66,67]. Unfortunately, these in- • the patient’s and family expectations of the epilepsy surgery, with struments are designed to detect symptoms and not to establish a respect to seizure outcome and changes in the patient’s quality of categorical diagnosis, let alone the diagnosis of psychiatric entities life, employment and potential cognitive risks. The evaluation may take 1–3 h, represents the most frequent methodological error in psychiatric depending on the complexity of the psychiatric history at hand and research studies in epilepsy. The argument for exclusively using may require two or three sessions with the psychiatrist. This type of ceptable levels of sensitivity and specifcity, and the severity of the evaluation can be ofen obtained from the hospital rehabilitation ther- depressive episodes. Tus, proponents of the sole use of these scales apists or from governmental agencies that work with disabled patients. To that end, any methodologically sound study tients with primary psychiatric disorders and not in patients with must include a structured psychiatric interview aimed at identify- epilepsy. The only exception is the Neurological Disorders De- ing lifetime psychiatric syndromes and personality disorders. Furthermore, structured interviews specifcally Clearly, the use of screening instruments for psychiatric research developed for patients with epilepsy will need to be elaborated in in epilepsy must be used in conjunction with a structured psychiat- the future. The scale consists of 21 items, each de- ure changes in severity of symptomatology. The most frequent- scribing a common symptom of anxiety over the past week on a ly used screening instruments in adults include the screening of four-point scale ranging from 0 (not at all) to 3 (severely – ‘I could general psychiatric, depressive, anxiety and obsessive–compulsive barely stand it’). Goldberg’s Depression and Anxiety Scales [87] consist of nine Screening of general psychiatric profles questions assessing mood and anxiety over the previous month; the The Adult Self-Report Inventories-4 are symptom inventories that full set of nine questions needs to be administered only if there are can be used as a guide for conducting clinical interviews [81]. The scales are devised specifcally include the behavioural symptoms of more than two dozen psychi- to be used by non-psychiatrists in clinical investigations. Tese invento- a 14-item clinical interview scale (not self-reported) measuring ries take approximately 15–20 min to complete. This instrument should be used with caution in to evaluate a broad range of psychopathology. It consists of 90 items patients with epilepsy, given the large number of somatic symptoms and can usually be completed in less than 30 min [82]. This scale has documented validity and der -7, is a seven item, self-rating instrument that screens for symp- has been in many treatment studies of mood disorders and schiz- toms of generalized anxiety disorder over the previous 2 weeks [89]. A score >10 is suggestive The Minnesota Multiphasic Personality Inventory consists of a of a diagnosis of generalized anxiety disorder. It takes 2–3 min to self-report personality inventory with 10 clinical scales (hypochon- complete. It in- cludes a symptom checklist as well as a 10-item scale that is rated by Depressive symptoms clinicians. The scale is sensitive to change and has been used in Self-report measures in paediatric patients clinical drug trials. Tere are Child is a composite of 20 items, rated from 0 (rarely) to 4 (most or all of Symptom Inventories for three diferent age groups: Early Child- the time). It can yield scores from 0 to 60, with scores >16 being hood Inventory-4 (ages 3–5 years), Child Symptom Inventory-4 suggestive of depressive illness. This scale has also been validated (ages 5–12 years) and Adolescent Symptom Inventory-4 (ages for its use in patients with epilepsy [80]. Tere is a self-report measure for adolescent pa- The Neurological Disorders Depression Inventory for Epilepsy tients: Youth’s Inventory-4 (ages 12–18 years) [91]. Achenbach, is a scale that evaluates pathological behaviours major depressive episodes in patients with epilepsy, while mini- and social competence in children from the ages of 4 to 16 years. Completing this instrument takes only of the most widely used scales for both clinical use and research 3 min or less and a score of >15 is suggestive of the presence of a [92]. Each question includes three statements Anxiety symptoms of increasing severity [93]. The 39 items are scored on a scale from 0 to 3 826 Chapter 64 as follows: 0 = never true about me; 1 = rarely true about me; 2 = children and the association (if any) of any previous psychiatric his- sometimes true about me; 3 = ofen true about me [94]. It is available in three versions: a 93-item of their risk factors, remains as well ‘terra incognita’ in desperate version, a 48-item version and a 10-item screening version. Yet, until adapted from the adult version, to assess obsessive–compulsive epilepsy teams fnd a way to integrate psychiatrists into their team symptoms [96].

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