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As the condition is potentially reversible blood pressure normal teenager effective 80mg verapamil, patients with any combination of the above symptoms should be treated with thiamine hypertension headaches order verapamil now. As little as 2mg of thiamine may be enough to blood pressure medication cause hair loss buy 80 mg verapamil with mastercard reverse the eye problems but initial higher doses of at least 100mg are advisable pulse pressure 86 cheap verapamil 240mg free shipping. The problems of gait and acute confusional state may improve dramatically although improvement may not be noted for days or months. Doctors will investigate the patients magnesium levels and correct any deficiency. There is some evidence that good social supports can bring a good social outcome in alcohol misue. There is some experience and evidence that memory rehabilitation and therapies may have be of some benefit to patients. These would include external aids like diaries and reminders; the use of mnemonics to help memory; attendance at memory groups. Referral of patients with alcoholism to drinking cessation programmes and monitoring them for signs of alcohol withdrawal is a key step in outpatient treatment. Migraine attacks with aura (visual misperceptions) precede the onset of cognitive impairment. Gertz et al: Nervenarzt 73 (2002) 393-404; Dichgans M: Cerebrovasc Dis 13 Suppl 2 (2002) 37-41. Binswanger disease by Jos Van der Poel General outlines Binswanger disease is a form of vascular dementia and was first described in 1894. The illness occurs mainly in middle-aged hypertensive patients who show evidence of systematic vascular disease and who develop insidious fluctuating dementia with special involvement of memory, mood and cognition; seizures and mild strokes. Pathological features: lacunes, subcortical white matter demyelination, neuronal loss, gliosis, ventricular dilatation and atheromatosis of the larger cerebral vessels. Olsen C, Clasen M; Senile dementia of the Binswanger’s typeAmerican Academy of Family Physisians, Dec. Synonyms Congophilic angiopathy Symptoms and course A combination of neurological and psychopathological symptoms. Cognition is about our abilities in thinking things through and how well our memory works. Cognition is also about how to focus and to maintain our attention; the way we learn and remember new things; how we think reason and solve problems. It also concerns how we plan and carry out our activities; the way we understand and use language and how well we recognise objects, assemble things together and judge distances. Although the problems may not amount to full dementia they can cause significant disruption to the lives of patients. Current research shows that the main determinant of the rate of cognitive decline is not the course of the disease but the extent of the development of brain lesions to the myelin. This can vary in patients with relapse/remission and those with a progressive condition. Follow up studies of patients’ show that in some people there has been no or little further cognitive decline after 2, 4 or 5 years. The key to coping with them is to understand and to accept what is happening as a result of the disease process and possibly make some changes to make life easier. Carers may become frustrated if the person doesn’t respond to a question as quickly as the person is being awkward but in fact they just cannot remember or think straight. The person may express anger about what is happening to them and take this out on the carer. Similarly the carer may also be angry or depressed about he person and possibly become irritable and withdrawn. This is part of the ‘white matter’ of the brain as opposed to the grey matter, which contains the nerve cells themselves. For the majority of these people the changes are mild to moderate rather than severeWhilst brain lesions can result in more permanent cognitive problems there are a several factors that can interfere with or impair cognition temporarily. Depression, stress, pain, tiredness and relapses can create temporary cognitive difficulties. Additional circumstances that can affect concentration, memory and learning include high alcohol consumption, poor nutrition and illnesses as well as medication that affects the central nervous system like tranquillisers, sleeping pills and painkillers. When patients experience cognitive problems it does not mean that they will experience all of them. There is much variation in the difficulties people experience and the impact it they will have on their lives. Learning and memory: the most common types of memory problems are remembering recent events and the need to do things. Some people say that it may take more time and effort to remember this affecting recall. Attention, concentration and mental sped: some people find it more difficult to concentrate for long periods of time or have trouble keeping track of what they are doing if interrupted. Problem solving: some people experience difficulties when making plans and solving problems. They know what they want to do but find it difficult to know where to start and what steps to take to achieve their aims. These have been the use of rating scales and direct computer assisted lesion volume measurement. Comprehensive neuropsychological testing can be complex for the purpose of cognitive screening. However combinations of tests (4, Rao) have been developed to examine long-term verbal and spatial memory,verbal fluency and speed of information processing. The assessment will consist of an interview about the past and present social functions and abilities of the person; a number of different verbal and written tests on attention, memory, problem solving and giving feedback on the results. The assessment will usually take between two and three hours with a follow-up session for feedback. The assessment should aim to identify the specific problems of the person and also their personal strengths to help them overcome and manage any weaknesses. Rehabilitation will aim to minimise the effects of problems with memory and thinking. It will include encouraging the person to practise and improve weakened skills; make better use of strengths; learn alternative and compensatory techniques; cope with limited abilities practically and emotionally and offer counselling to relatives. Voluntary agencies have further information of hints and tips for coping with cognitive problems. Worthy of note here is a major international review of research published in November 2002 which was highly critical of three decades of research effort. Available services Voluntary organisations can provide advice, support and practical help in a range of areas: Multiple Sclerosis International Federation Foong, J et al A comparison of neuropsychological deficitis in primary and secondary multiple sclerosis. Bakker S, Boon A, Wijnhoud A, Dippel D, Delwel E, Koudstaal P; Cerebral hemodynamics before and after shunting in normal pressure hydrocephalusActa Neurologica Scandinavia, 2002, 106(3), 123-7 2. Tans J, Boon A; How to select patients with normal pressure hydrocephalus for shuntingActa Neurochirurgica Supplement, 2002, 81, 3-5 3. Nakamizo A et al; Occurrence of subdural hematoma and resolution of gait disturbance in a patient treated with shunting for normal pressure hydrocephalus Clinical Neurology and Neurosurgery, 2002, 104, 315-317 6. Savolainen S et al; Five-year outcome of normal pressure hydrocephalus with or without a shunt: pedictive value of the clinical signs, neurophysological evaluation and infusion test Acta Neurochirurgica, 2002, 144: 515-523 7. Bateman G; Pulse-waved encephalopathy: a comparative study of the hydrodynamics of leukoaraiosis and normal-pressure hydrocephalus Neuroradiology. Mitchell P, Mathew B; Third ventriculostomy in normal pressure hydrocephalusBritisch Journal of Neurosurgery, August 1999 9. Found throughout the brain, acetylcholine enables nerve cells to communicate with each other. Its function is unknown and it may be the cause of the deterioration of brain function. Amyloid plaques are one of the characteristic structural abnormalities found in the brains of individuals with Alzheimer’s. Upon autopsy, the presence of amyloid plaques and neurofibrillary tangles is used to positively diagnose Alzheimer’s. The production of antibodies is the first line of defense in the body’s immune response. Autopsy is often performed (upon request) to confirm a diagnosis of Alzheimer’s disease.

Nonrenal disease activity fol- lowing mycophenolate mofetil or intravenous cyclophosphamide as induction treatment for lupus nephritis: fndings in a multicenter arrhythmia treatment algorithm 80 mg verapamil sale, prospective blood pressure chart elderly best verapamil 240 mg, randomized blood pressure medication lightheadedness purchase verapamil cheap, open-label hypertension categories cheap verapamil 240 mg overnight delivery, parallel-group clinical trial. The cutaneous lupus erythematosus disease area and severity index: a responsive instrument to measure activity and dam- age in patients with cutaneous lupus erythematosus. The Cutaneous Lupus Erythematosus Disease Activity and Severity Index: expansion for rheumatology and derma- tology. The study of Cutaneous Lupus Erythematosus Disease Area and Severity Index in Indian patients with systemic lupus ery- thematosus. Discoid lupus erythematosus: diagnostic features and evaluation of topical corticosteroid therapy. Topical tacrolimus and pimecrolimus in the treatment of cutaneous lupus erythematosus: an evidence-based evaluation. Topical tacrolimus therapy of resistant cutaneous lesions in lupus erythematosus: a possible alternative. Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus A meta-analysis. Evidence- based recommendations for the prevention and long-term management of thrombosis in antiphos- pholipid antibody-positive patients: report of a task force at the 13th International Congress on an- tiphospholipid antibodies. Clinical effcacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Effcacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies: an international and collaborative meta-analysis. A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus ne- phritis. Pregnancy and renal outcomes in lupus nephritis: an update and guide to management. The second trimester Doppler ultrasound examination is the best predictor of late pregnancy outcome in systemic lupus erythematosus and/or the antiphospholipid syndrome. Ocular toxicity in children exposed in utero to antimalarial drugs: review of the literature. Disease- modifying antirheumatic drugs in pregnancy: current status and implications for the future. Pregnancy outcome following in utero expo- sure to hydroxychloroquine: a prospective comparative observational study. Recurrent Pregnancy Loss With Antiphospholipid Antibody: A Systematic Review of Therapeutic Trials. Risk factors associated with fetal losses in treated antiphospholipid syndrome pregnancies: a multivariate analysis. Prevention of recurrent miscarriage for women with an- tiphospholipid antibody or lupus anticoagulant (Review). Brief report First-trimester low- dose prednisolone in refractory antiphospholipid antibody related pregnancy loss. Ovulation induction and in vitro fertilization in systemic lupus erythematosus and antiphospholipid syndrome. Importance of planning ovulation induction therapy in systemic lupus erythematosus and antiphospholipid syn- drome: a single center retrospective study of 21 cases and 114 cycles. Contraceptive counseling and use among women with systemic lupus erythematosus: a gap in health care qualityfi Pregnane progestin contraception in systemic lupus erythematosus: a longitudinal study of 187 patients. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus ery- thematosus. Effect of rheumatoid arthritis or systemic lupus erythematosus on the risk of First-Time acute myocardial infarction. Cardiovascular event in systemic lupus erythematosus in northern Sweden: Incidence and predictors in a 7-year follow-up study. Increased Risk of Ischemic Stroke in Patients with Systemic Lupus Erythematosus: A Nationwide Population-based Study. Risk factors for development of coronary artery disease in women with systemic lupus erythematosus. Incidence of and risk factors for adverse cardiovascular events among patients with systemic lupus erythematosus. Age-specifc incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Incidence and risk factors of thromboembolism in systemic lupus erythematosus: a comparison of three ethnic groups. Differences in subclinical cardiovascular disease between African American and Caucasian women with systemic lupus erythematosus. Frequency of established cardiovascular disease and its risk factors in Chinese patients with systemic lupus erythematosus. Evaluation of Risk Factors That Contribute to High Prevalence of Premature Atherosclerosis in Chinese Premenopausal Systemic Lupus Erythematosus Patients. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. Factors involved in the progress of preclinical atherosclerosis associated with systemic lupus erythematosus: a 2-year longitudinal study. Premature aortic atherosclerosis in systemic lupus erythematosus: a controlled transesophageal echocardiographic study. Subclinical atherosclerosis and endothe- lial dysfunction in young South-Asian patients with systemic lupus erythematosus. Predictors of the frst cardiovascular event in patients with systemic lupus erythematosus a prospective cohort study. A panel of biomarkers is associated with increased risk of the presence and progression of atherosclerosis in women with systemic lupus erythematosus. Use of a strategy based on calculated risk scores in managing cardiovascular risk factors in a large British cohort of patients with systemic lupus erythematosus. Cardiovascular risk in rheumatoid arthritis and sys- temic autoimmune rheumatic disorders: a suggested model of preventive strategy. Changes in lipid profle between fare and remission of patients with systemic lupus erythematosus: a prospective study. Risk factors for coronary artery disease in pa- tients with systemic lupus erythematosus. Lipid and lipoprotein levels in premenopau- sal systemic lupus erythematosus patients. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by re. Cardiovascular risk in systemic lupus erythe- matosus-evidence of increased oxidative stress and dyslipidaemia. Hyperinsulinemia, Insulin Resistance, and Circulating Oxidized Low Density Lipoprotein in Women with Systemic Lupus Erythematosus Guidelines of the National Cholesterol Education Program. Proinfammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythema- tosus and rheumatoid arthritis. Lipoprotein subclasses and particle size determined by nuclear magnetic resonance spectroscopy in systemic lupus erythematosus. The apolipopro- tein E2 isoform is associated with accelerated onset of Coronary Artery Disease in Systemic Lupus Erythematosus. Anti-(apolipoprotein A-1) IgGs are associated with high levels of oxidized low-density lipoprotein in acute coronary syn- drome. Coronary artery disease risk factors in the Johns Hopkins Lupus Cohort: prevalence, recognition by patients, and preventive practices. Angiotensin inhibition or blockade for the treatment of patients with quiescent lupus nephritis and persistent proteinuria. Clinical and immunogenetic factors associated with pneumonia in patients with systemic lupus ery- thematosus: a case-control study. Recommended Adult Immunization Schedule — United States, October 2005 September 2006 QuickGuide. Vaccination in adult patients with auto-immune infammatory rheumatic diseases: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for vaccination in adult patients with auto-immune infammatory rheuma. A controlled study of pneumococcal in polysaccharide vaccine systemic lupus erythematosus. Pneumococcal immunization in patients with systemic lupus erythematosus treated with immunosuppressives.

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In consideration of its origin we speak of this latter portion of the id as the repressed hypertension untreated discount verapamil 80 mg visa. It is of little importance that we are not always able to pulse pressure heart cheap verapamil 80mg overnight delivery draw a sharp line between these two categories of contents in the id blood pressure herbs buy generic verapamil 120 mg on-line. They coincide approximately with the distinction between what was innately present originally and what was acquired in the course of the ego’s development arrhythmia nursing care plan discount 120mg verapamil visa. Having now decided upon the topographical dissection of the psychical apparatus into an ego and an id, with which the difference in quality between preconscious and unconscious runs parallel, and having agreed that this quality is to be regarded only as an indication of the difference and not as its essence, a further question faces us. What, if this is so, is the true nature of the state which is revealed in the id by the quality of being unconscious and in the ego by that of being preconscious and in what does the difference between them consistfi And the profound obscurity of the background of our ignorance is scarcely illuminated by a few glimmers of insight. We assume, as other natural sciences have led us to expect, that in mental life some kind of energy is at work; but we have nothing to go upon which will enable us to come nearer to a knowledge of it by analogies with other forms of energy. We seem to recognize that nervous or psychical energy occurs in two forms, one freely mobile and another, by comparison, bound; we speak of cathexes and hypercathexes of psychical material, and even venture to suppose that a hypercathexis brings about a kind of synthesis of different processes a synthesis in the course of which free energy is transformed into bound energy. At any rate, we hold firmly to the view that the distinction between the unconscious and the preconscious state lies in dynamic relations of this kind, which would explain how it is that, whether spontaneously or with our assistance, the one can be changed into the other. An Outline Of Psycho-Analysis 4974 Behind all these uncertainties, however, there lies one new fact, whose discovery we owe to psycho- analytic research. We have found that processes in the unconscious or in the id obey different laws from those in the preconscious ego. We name these laws in their totality the primary process, in contrast to the secondary process which governs the course of events in the preconscious, in the ego. In the end, therefore, the study of psychical qualities has after all proved not unfruitful. The only thing that can help us are states of conflict and uproar, when the contents of the unconscious id have a prospect of forcing their way into the ego and into consciousness and the ego puts itself once more on the defensive against this invasion. It is only under these conditions that we can make such observations as will confirm or correct our statements about the two partners. Now, our nightly sleep is precisely a state of this sort, and for that reason psychical activity during sleep, which we perceive as dreams, is our most favourable object of study. In that way, too, we avoid the familiar reproach that we base our constructions of normal mental life on pathological findings; for dreams are regular events in the life of a normal person, however much their characteristics may differ from the productions of our waking life. Dreams, as everyone knows, may be confused, unintelligible or positively nonsensical, what they say may contradict all that we know of reality, and we behave in them like insane people, since, so long as we are dreaming, we attribute objective reality to the contents of the dream. We find our way to the understanding (‘interpretation’) of a dream by assuming that what we recollect as the dream after we have woken up is not the true dream-process but only a facade behind which that process lies concealed. Here we have our distinction between the manifest content of a dream and the latent dream-thoughts. The process which produces the former out of the latter is described as the dream- work. The study of the dream-work teaches us by an excellent example the way in which unconscious material from the id (originally unconscious and repressed unconscious alike) forces its way into the ego, becomes preconscious and, as a result of the ego’s opposition, undergoes the changes which we know as dream-distortion. An Outline Of Psycho-Analysis 4976 It is best to begin by pointing out that the formation of a dream can be provoked in two different ways. Either, on the one hand, an instinctual impulse which is ordinarily suppressed (an unconscious wish) finds enough strength during sleep to make itself felt by the ego, or, on the other hand, an urge left over from waking life, a preconscious train of thought with all the conflicting impulses attached to it, finds reinforcement during sleep from an unconscious element. The mechanism of dream-formation is in both cases the same and so also is the necessary dynamic precondition. The ego gives evidence of its original derivation from the id by occasionally ceasing its functions and allowing a reversion to an earlier state of things. This is logically brought about by its breaking off its relations with the external world and withdrawing its cathexes from the sense organs. We are justified in saying that there arises at birth an instinct to return to the intra-uterine life that has been abandoned an instinct to sleep. Since the waking ego governs motility, that function is paralysed in sleep, and accordingly a good part of the inhibitions imposed on the unconscious id become superfluous. The withdrawal or reduction of these ‘anticathexes’ thus allows the id what is now a harmless amount of liberty. The evidence of the share taken by the unconscious id in the formation of dreams is abundant and convincing. Dreams bring up recollections which the dreamer has forgotten, which are inaccessible to him when he is awake. That explains the help usually indispensable given us by dreams in the attempts we make during the analytic treatment of neuroses to reconstruct the dreamer’s early life. We are obliged to regard it as part of the archaic heritage which a child brings with him into the world, before any experience of his own, influenced by the experiences of his ancestors. We find the counterpart of this phylogenetic material in the earliest human legends and in surviving customs. An Outline Of Psycho-Analysis 4977 But what makes dreams so invaluable in giving us insight is the circumstance that, when the unconscious material makes its way into the ego, it brings its own modes of working along with it. This means that the preconscious thoughts in which the unconscious material has found its expression are handled in the course of the dream-work as though they were unconscious portions of the id; and, in the case of the alternative method of dream-formation, the preconscious thoughts which have obtained reinforcement from an unconscious instinctual impulse are brought down to the unconscious state. It is only in this way that we learn the laws which govern the passage of events in the unconscious and the respects in which they differ from the rules that are familiar to us in waking thought. Thus the dream-work is essentially an instance of the unconscious working-over of preconscious thought-processes. To take an analogy from history: invading conquerors govern a conquered country, not according to the judicial system which they find in force there, but according to their own. It is, however, an unmistakable fact that the outcome of the dream- work is a compromise. The ego-organization is not yet paralysed, and its influence is to be seen in the distortion imposed on the unconscious material and in what are often very ineffective attempts at giving the total result a form not too unacceptable to the ego (secondary revision). In our analogy this would be an expression of the continued resistance of the defeated people. An Outline Of Psycho-Analysis 4978 the laws that govern the passage of events in the unconscious, which come to light in this manner, are remarkable enough and suffice to explain most of what seems strange to us about dreams. Above all there is a striking tendency to condensation, an inclination to form fresh unities out of elements which in our waking thought we should certainly have kept separate. As a consequence of this, a single element of the manifest dream often stands for a whole number of latent dream-thoughts as though it were a combined allusion to all of them; and in general the compass of the manifest dream is extraordinarily small in comparison with the wealth of material from which it has sprung. Another peculiarity of the dream-work, not entirely independent of the former one, is the ease with which psychical intensities (cathexes) are displaced from one element to another, so that it often happens that an element which was of little importance in the dream-thoughts appears as the clearest and accordingly most important feature of the manifest dream, and, vice versa, that essential elements of the dream-thoughts are represented in the manifest dream only by slight allusions. Moreover, as a rule the existence of quite insignificant points in common between two elements is enough to allow the dream-work to replace one by the other in all further operations. It will easily be imagined how greatly these mechanisms of condensation and displacement can increase the difficulty of interpreting a dream and of revealing the relations between the manifest dream and the latent dream-thoughts. From the evidence of the existence of these two tendencies to condensation and displacement our theory infers that in the unconscious id the energy is in a freely mobile state and that the id sets more store by the possibility of discharging quantities of excitation than by any other consideration;fi and our theory makes use of these two peculiarities in defining the character of the primary process we have attributed to the id. An Outline Of Psycho-Analysis 4979 the study of the dream-work has taught us many other characteristics of the processes in the unconscious which are as remarkable as they are important; but we must only mention a few of them here. The governing rules of logic carry no weight in the unconscious; it might be called the Realm of the Illogical. Urges with contrary aims exist side by side in the unconscious without any need arising for an adjustment between them. Either they have no influence whatever on each other, or, if they have, no decision is reached, but a compromise comes about which is nonsensical since it embraces mutually incompatible details. With this is connected the fact that contraries are not kept apart but treated as though they were identical, so that in the manifest dream any element may also have the meaning of its opposite. Certain philologists have found that the same held good in the most ancient languages and that contraries such as ‘strong-weak’, ‘light-dark’ and ‘high-deep’ were originally expressed by the same roots, until two different modifications of the primitive word distinguished between the two meanings. Residues of this original double meaning seem to have survived even in a highly developed language like Latin in its use of words such as ‘altus’ (‘high’ and ‘deep’) and ‘sacer’ (‘sacred’ and ‘infamous’). In view of the complication and ambiguity of the relations between the manifest dream and the latent content lying behind it, it is of course justifiable to ask how it is at all possible to deduce the one from the other and whether all we have to go on is a lucky guess, assisted perhaps by a translation of the symbols that occur in the manifest dream. It may be said in reply that in the great majority of cases the problem can be satisfactorily solved, but only with the help of the associations provided by the dreamer himself to the elements of the manifest content. But the dreamer’s associations bring to light intermediate links which we can insert in the gap between the two and by aid of which we can reinstate the latent content of the dream and ‘interpret’ it. It is not to be wondered at if this work of interpretation (acting in a direction opposite to the dream-work) fails occasionally to arrive at complete certainty.

Targeted treatment of pyo- Blau syndrome does not result in excess interleukin-1 activity blood pressure chart for 80 year old woman discount verapamil master card. Pediatr Dermatol 2005; Hematopoietic stem cell transplantation rescues the immunologic phenotype and 22:262-5 blood pressure of 80/50 buy verapamil 120mg mastercard. Peridis S blood pressure 120 80 buy online verapamil, Pilgrim G blood pressure yogurt safe 80mg verapamil, Koudoumnakis E, Athanasopoulos I, Houlakis M, Parpounas muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy. Strobel S, Abarrategui-Garrido C, Fariza-Requejo E, Seeberger H, Sanchez- complement components in systemic lupus erythematosus. Mannan-binding lectin insufficiency in children with recurrent infections autoantibodies. You are encouraged to always fully discuss any blood test results with your doctor or healthcare team. For example, there are no blood tests to diagnose you are getting better and infammation is reducing. Your doctor will use blood tests to help confrm what they fnd on examination and from listening to College of Rheumatology, approximately 95% of your symptoms. The blood tests used to check for common types of arthritis include: 1800 011 041 Rheumatoid factor is an antibody (a protein in 8% of the general population, including healthy made by the body’s immune system). For more information: Books: Upfal, Jonathan & O’Callaghan, Jill 2001, Your medical this information sheet was produced in association with the Royal tests: What do they meanfi Websites: Lab Tests Online – information about various laboratory tests and how they are used. Source: A full list of the references used to compile this sheet is available from your local Arthritis Ofce The Australian General Practice Network, Australian Physiotherapy Association, Australian Practice Nurses Association, Pharmaceutical Society of Australia and Royal Australian College of General Practitioners contributed to the development of this information sheet. Your local Arthritis Office has information, education and support for people with arthritis Helpline 1800 011 041 The availability of considered in more detail here, as they are by far the most antisera, im m unoglobulin fractions and m onoclonal anti- frequently utilized antibodies in im m unohistochem istry. Digestion by papain results in the cleavage of a susceptible bond on Antibodies belong to a group of proteins called the N-term inal side of the inter-heavy chain disulfide im m unoglobulins (Ig). This yields two m onovalent antigen-binding frag- quantity found in plasm a or serum, the im m unoglobulins m ents (Fab) and one crystalline fragm ent (Fc). Pepsin comprise five major classes: immunoglobulin G (IgG), IgA, cleaves the gam m a chains on the C-term inal side of the IgM, IgD and IgE. Each immunoglobulin is composed of two inter-heavy chain disulfide bridges, resulting in one biva- identical heavy chains (H) and two identical light chains (L). In this case, the Fc 2 the H chains differ in antigenic and structural properties fragm ents are destroyed. Reductive dissociation of an IgG and determine the class and subclass of the molecule. The m olecule splits the interchain disulfide bridges and, if the two L chains are either type kappa or lambda. The distribu- free sulfhydryl groups are blocked, results in the form ation tion of kappa and lambda chains differs in all Ig clases and of two H chains (m olecular weight 50 kD each) and two L subclasses, as well as between different species. By participating in the tertiary structure, they confer greater the IgG m olecule can be further divided into so-called stability to the immunoglobulin molecule. It com prises two identical heavy (H) chains and two identical light (L) Figure 2: Diagram showing the structure of rabbit IgG (which exists as a chains. Inter- and intrachain disulfide bonds contribute to the single major subclass). The heavy (H) and light (L) chains are composed of structure and stability of the m olecule. Proteolytic digestion with papain *It should be understood that the term “immunohistochemistry” as used in yields two antigen-binding fragments (Fab) and one crystalline fragment this chapter, denotes and includes the term “immunocytochemistry” also. In this region, A unique structural specificities called idiotypic determinants are located. M inor differences within these hinge regions contribute to the subclass speci- ficity of im m unoglobulin G. B W hereas in human IgG the overall ratio of kappa to lambda Figure 3: Diagram showing (A) the five subunits of m ouse IgM linked is 2:1, in the subclasses IgG2 and IgG4 for exam ple the by disulfide bridges and the J chain to form a pentam eric ring structure. Each subunit (B) com prises two m u heavy (H) chains and two ratios are 1:1 and 8:1, respectively. M ice have approxi- light (L) chains each com posed of constant (C) and variable (V) mately 95% kappa chains and therefore most monoclonal dom ains. The num ber of disulfide bridges linking the heavy chains also W hereas IgG is the m ost abundant antibody in the hyper- varies am ongst the IgG subclasses. IgG1 and IgG4 each im m unized host, in the newly im m unized anim al, IgM is the have two, while IgG2 and IgG3 have four and five, respec- first hum oral antibody detectable. Because of the flexibility of the hinge region, the form ation proceeds in several m ajor stages. Injected angle that both Fab fragm ents form can vary to accom im m unogen first reaches equilibrium between extra- and m odate varying distances between identical antigenic intravascular spaces, then undergoes catabolism resulting determ inants. The IgM IgM is a pentam er (M W approxim ately 900 kD) period from the introduction of an im m unogen until the first consisting of five subunits of approxim ately 180 kD each appearance of hum oral IgM antibodies is called the latent (Figure 3). The general formula can be expressed as (mu2 period and m ay last approxim ately one week. Each subunit is linked by a weeks, or in response to a second injection, IgG class anti- 2 2 2 sulfhydryl-rich peptide, the J chain (15 kD), and consists of bodies usually predom inate. Like all proteins, antibodies two heavy chains (mu) and two light chains of type kappa or are subject to catabolism. The J-chains contribute to the integrity and stability IgM have a relatively short half-life of only four to six days, of the pentam er. Unless repeated booster injections with the 2 Fab and Fc portions, as well as heavy and light chains, im m unogen are given, the serum antibody level will respectively. Treatment of pen- Antibody form ation on the m olecular level is a com plex tameric IgM with 0. The interested reader is referred to the Subclasses of IgM1 and IgM2 have been reported. After the rem oval of cells from the Polyclonal antibodies are produced by different cells, blood, polyclonal antibodies can be obtained either in the and in consequence, are im m unochem ically dissim ilar; form of stabilized antisera or as im m unoglobulin fractions they react with various epitopes on the antigen against purified to varying degrees. By far, the most frequently by ion exchange chrom atography, serves to rem ove the used anim al for the production of polyclonal antibodies is bulk of other serum proteins. Affinity chrom atography can the rabbit, followed by goat, pig, sheep, horse, guinea pig and others. The popularity of rabbits for the production of be used to isolate the antigen-specific antibodies and there- polyclonal antibodies is attributed prim arily to their easy by free them of cross-reacting antibodies to other species. In addi- tion, rabbit antibodies precipitate hum an proteins over a M onoclonal antibodies are the product of an individual wider range of antigen or antibody excess and pools of clone of plasm a cells. Antibodies from a given clone are antibodies made from many rabbits are less likely to result im m unochem ically identical and react with a specific epi- in m ajor batch-to-batch variations than pools m ade from tope on the antigen against which they are raised (Figure only a few, larger animals. Probably for reasons of econom y, m ice are currently ing for favorable immunization response has made the New used alm ost exclusively for the production of m onoclonal Zealand W hite rabbit the m ost frequently used anim al for 2 antibodies. After an im m une response has been achieved, the production of polyclonal antibodies. B lym phocytes from spleen or lym ph nodes are harvested and fused with non-secreting m ouse m yelom a cells under specific conditions. W hile the B lym phocytes convey the specific antibody, m yelom a cells bestow upon the hybrid cells (hybridom a) longevity in culture m edium. Non- reactive B cells and m yelom a cells are discarded and the antibody-producing hybridom a is cultured and tested for desired reactivity. Propagation can be carried out in culture m edium or by transplantation of the hybridom a into the peritoneal cavity of syngeneic m ice from where the antibodies are harvested in ascites fiuid. Thus, large and, at least theoretically, unlim ited quantities of m onoclonal antibodies of specific characteristics can be produced. Figure 4: Schem atic diagram of polyclonal antibodies binding to various epitopes on an antigen. Depending on the immunogenicity of the antigen, doses of from 10 µg to 200 µg are traditionally adm inistered to generate an im m une response in anim als. The antigen is m ost often injected intraderm ally or subcutaneously, but injections into the footpad m uscle or peritoneal cavity are also used. Booster shots, repeated once a month or when decreasing titers are noted, are intended to maintain or increase antibody levels.