Most Effective Autoimmune Diseases Treatments

The Autoimmunity Bible & Norton Protocol

A former autoimmunity (lupus) sufferer and alternative health specialist teaches you how to: Eradicate your autoimmune disease by addressing the single most important chemical imbalance on the cellular level as per groundbreaking new discoverie in the field. Avoid the traps that your adrenal glands set for you once you start using steroids. This reaction has been found to be responsible for autoimmunity flares in 81% of cases according to recent studies. If your disease caused a rash, now you can clear it out by getting rid of it's underlying triggers. Gain instant relief within 4 days to a week. Eliminate the debilitating life-altering pain in your joints and re-claim your life from the claws of autoimmunity. Eliminate the 2 overlooked obstacles that make any healing agent futile if your are suffering from an autoimmune disease. This is exactly why no drugs can cure autoimmune disorders. It's like pouring water into a hollow bucket. Reverse the processes that are most likely scavenging your kidneys.

The Autoimmunity Bible & Norton Protocol Summary

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Complement and Autoimmunity

Abstract The role of complement in the regulation of the immune response has been studied extensively (1) and is reviewed elsewhere in this book. At the mature B cell level, complement 3 products bind to complement receptor 2 (CR2) expressed on the surface of B and dendritic cells and facilitate antigen localization and process, lowering the excitation threshold and deferring apoptosis. In this chapter we will discuss the impact of complement component deficiency in man and mouse on the development of autoimmunity. Differences between mice and humans will become apparent and the dual effect of complement as effector of tissue pathology and controller of the development of the immune cell repertoire will emerge.

Complement Component Deficiency And Autoimmunity In Humans

Genome wide studies of human systemic and autoimmunity have unequivocally revealed that the number of loci associated with the development of clinical disease are multiple (1-3). It can be assumed therefore, that the number of the involved genes is rather large confirming a long suspected conviction that human systemic autoimmunity is multigenic in origin. In contrast to this position have been reports of the development of systemic autoimmune disease in rare patients who miss several complement proteins. It has long been realized that deficiencies of the early components of complement pathway are associated with the autoimmune manifestations, whereas deficiency of the so-called common pathway of the complement activation is associated with infections. Almost all individuals deficient in C1q, C2 and C4 components of the complement develop either SLE or glomerulonephritis. The number of the reported cases with Table 1. Autoimmune diseases in complete complement Table 1. Autoimmune...

The Complex Roles of Anaphylatoxins in Allergic Asthma and Autoimmune Diseases

Abstract Complement has a long-recognized role as a lytic effector system that protects against microbial pathogens as well as a mediator of acute and chronic inflammatory responses. Many of the inflammatory properties related to complement activation can be related to the complement cleavage fragments C3a and C5a, the so-called anaphylatoxins. Cloning and subsequent gene targeting of their corresponding receptors, as well as generation of specific C3a and CSa inhibitors, have fueled new interest in studies aimed at defining the roles of the anaphylatoxins in inflammatory diseases. Traditionally, the anaphylatoxins have been considered mediators of end-stage effector mechanisms. However, recent data from animal models of allergic asthma suggest that C3a and C5a provide a critical link between innate and adaptive immunity. Further, the anaphylatoxins appear to form a sophisticated regulatory network together with immunoglobulin G Fc receptors that links regulatory events with effector...

Myasthenia Gravis in the Intensive Care Unit

It is very rare for myasthenia gravis to present initially with such severity as to require intensive care. In a study of 1036 patients followed between 1940 and 1980, only 1 presented with dyspnoea.52 There are two common situations in which intensivists encounter patients with myasthenia gravis. The first is during the pre- and postoperative management of patients undergoing a thymectomy. In some centres, even well patients are treated aggressively with plasma exchange prior to thymectomy. The procedure may be transcervical,53 in which case there is a danger of leaving thymic tissue, or transsternal, which carries a slightly greater morbidity.54 After the procedure, there is usually a dramatic symptomatic improvement within 24 h which lasts for a few days. The most common presentation of myasthenia gravis to the intensive care unit is rapidly progressive bulbar or respiratory failure in a patient in whom the diagnosis has previously been established. This is usually due to a...

Myasthenia Gravis

Myasthenia gravis is an autoimmune disease. It can occur at any age and is more common in women. There are some genetic associations, but usually it is sporadic. In myasthe-nia gravis, acetylcholine receptor antibodies decrease post-synaptic receptor activity at the neuromuscular junction. The muscle cannot receive the message propagated by the action potential. The clinical effect is muscle weakness, which may be variable, chronic, localized, or diffuse. The immunologic component (B and T cells produced in thymus) plays a role. About 75 of patients have thymic abnormalities, and 10 have thymomas. Common ocular findings include unilateral or bilateral ptosis, which is usually asymmetric lid fasciculations, and lid retraction. Patients with myasthenia gravis frequently have eye muscle deviations with double vision. Systemic manifestations include involvement of the jaw and neck, inability to hold the body erect because of weakness of the spinal muscles, and limb weakness. In addition,...

Cytokine Chemokine and Inflammatory Mediator Receptors

Most of the cytokine receptors are transmembrane proteins, although in some cases measurable (even high) levels of circulating, soluble forms (extracellular domains) of the receptors are observed (eg, soluble TNFRs, IL-2Rs, IL-4Rs, and IL-6Rs).8-10 Soluble cytokine receptors may regulate cytokine actions by specifically binding their cognate cytokine and thus inhibiting its interaction with receptors expressed on target cells.2 Alternatively, soluble receptors may potentiate the effects of their bound cytokine by extending its half-life in the circulation.2 The failure to control the levels of circulating cytokines may contribute to pathological situations including sepsis, tissue damage, inflammation, and autoimmunity.

Alexias And Agraphias Languagerelated Disorders

Lips and impairs enunciation of labial consonants (B, M, P). Neurological examination may reveal atrophy and fasciculations of the tongue and weakness of the palate and the facial muscles. When a history of variable dysarthria or dysphonia, with prominent fatigability is elicited, a neuromuscular junction disorder such as myasthenia gravis may be present.

Evaluation Guidelines Table95

AT, Ataxia-telangiectasia CSF, cerebrospinal fluid CT, computed tomography EMG, electromyography HD, Huntington's disease HIV, human immunodeficiency virus MG, myasthenia gravis MRA, magnetic resonance angiography MRI, magnetic resonance imaging N A, not applicable NCV, nerve conduction velocity TFTs, thyroid function tests. AT, Ataxia-telangiectasia CSF, cerebrospinal fluid CT, computed tomography EMG, electromyography HD, Huntington's disease HIV, human immunodeficiency virus MG, myasthenia gravis MRA, magnetic resonance angiography MRI, magnetic resonance imaging N A, not applicable NCV, nerve conduction velocity TFTs, thyroid function tests.

Diathesisstress Models

For instance, exposure to stressors for some individuals produces gastrointestinal (GI) dysfunction (ulcers, colitis, etc.), while others may manifest immunological disturbances (frequent infection due to stress-induced immunosuppression, increased occurrence or worsening of autoimmune diseases, etc.). Such disparities in physiological outcomes of stressor exposure has led many researchers to postulate that individuals vary in the organs or brain systems that are constitutionally weakest and thus more susceptible to adverse health outcomes during times of stress. In this regard, one could attempt to explain the recurrence of chronic colitis in relation to stressor exposure by

Antinuclear Antibodies

Although the ANA is 95 sensitive for systemic lupus erythematosus (SLE), it is not specific and is seen in other diseases. Higher titers are more specific for SLE but may be seen in the other autoimmune diseases. About 20 of normal people have an ANA titer of 1 40 or higher, and 5 have a titer of 1 160 or higher. Less than 5 of patients with definite SLE have a negative ANA titer. Because of the high prevalence of positive ANAs in normal people, physicians need to reserve the diagnosis of SLE for patients who have clinical findings compatible with SLE. ANA titers correlate poorly with relapses, remission, and severity of disease and are not helpful in monitoring the course or response to therapy. ANA testing should be ordered when a connective tissue disease is considered, but it is not generally helpful in the evaluation of nonspecific complaints, such as fatigue or back pain (Solomon et al., 2002).

Hif And Hematopoiesis

Hypoxia plays an important role in later stages of hematopoietic development as well. For example, we expect to observe similar defects in the para-aortic region within the early embryo. Our preliminary experiments indicate that indeed para-aortic hematopoietic progenitors and endothelial precursors are also deficient in Arnt--embryos. At later stages of development, blood cells are exposed to low O2 tensions as they migrate between blood and different tissues. Recent studies have shown that HIF-1a- - lymphocytes exhibit defects in differentiation and function, and HIF-1a deficiency in Rag2- -chimeras results in an elevation in the number of peritoneal B1-like lymphocytes that express high levels of B220 on their surface (Kojima et al. 2002). Such animals display autoimmunity with the accumulation of anti-dsDNA antibodies and rheumatoid factor in serum and deposits of IgG and IgM in the kidney. In conclusion, hy-poxia regulates hematopoietic tissue homeostasis in a HIF-dependent...

Epidemiology and Presentation

Outside the United States, the most common cause of pleural disease is tuberculosis. In the United States, TB is still significant, but other disorders, such as pneumonia, HIV-related infections, connective tissue disease (especially lupus), and malignancies (mesothelioma, peripheral lung cancer) must also be considered. Pleural effusions can be caused by systemic sources of transudate (CHF, hepatic failure with ascites, autoimmune disease) or by local inflammatory processes (parapneumonic effusion, pancreatitis, neoplasia).

New Insights Into the Regulation of Complement Activation by Decay Accelerating Factor

Abstract Decay-accelerating factor (DAF), a ubiquitously expressed GPI-anchored protein, is an intrinsic regulator of complement activation that acts to dissociate autologous C3 and C5 convertases that assemble on self cells. DAF contains four 60 amino acid long repeats termed short consensus repeats (SCRs) or complement control protein repeats (CCPs), followed by a serine threonine (S T)-rich region which in turn is attached to a posttranslationally-added glycosylphosphatidylinositol (GPI)-anchor. Studies with CCP deletion mutants showed that CCPs 2 and 3 are required for classical pathway (CP) function while CCP4 is additionally required for alternative pathway (AP) function. Mutagenesis studies based on a model built from the NMR structure of homologous CCPs indicated that positively charged amino acids (R , R , and R in CCP2, and K127 in the CCP2-CCP3 linker) and hydrophobic residues primarily in CCP3 (F148, F169, and L171) are important for DAF's function in one or both pathways....

Animal Models Of Disease

Unlike humans, in the mouse there are two Daf genes, Daf1 and Daf2. The Daf1 gene, like the human DAF gene, encodes GPI-anchored DAF that is ubiquitously expressed, while the Daf2 gene encodes transmembrane anchored DAF that is restricted in its distribution to the testes and spleen (Lin et al., 2001). Consequently for an animal model, the Daf1 gene was targeted. Daf1 knock-out mice (Lin et al., 2001 Miwa, 2001) provide a resource for studying several experimental animal models of disease including experimental autoimmune myasthenia gravis (EAMG), a murine model of systemic lupus erythrematosus (SLE) in MRL lpr mice, acute nephrotoxic serum (NTS)-induced nephritis, and dextran sodium sulfate (DSS)-induced colitis. In EAMG, the binding of anti-acetylcholine receptor (AChR) antibodies to the post-synaptic junction activates the classical pathway, ultimately leading to endplate damage (De Baets et al., 2003). Following anti-AChR mAb administration, as compared with Dafl* + littermates...

Fetal Tolerance And Complement

Helper 2-type (Th2-type) immunity and successful pregnancy, whereas Th1-type immune reactivity is associated with pregnancy loss (12). Fetomaternal tolerance is partially dependent on the secretion of immunoregulatory cytokines, such as TGF-P and IL-10, by the decidua and placenta (13-16). These cytokines may promote the development of Th2-type cells and regulatory T cells that provide immunosuppressive mechanisms important in fetal survival. Conditions associated with recurrent spontaneous miscarriages and preterm labor are associated with an inflammatory reaction, the production of proinflammatory cytokines such as TNF-a IL-6, IL-1, and INF-7, and a conversion from a Th2 to a Th1 phenotype (14, 17). That autoimmune disorders, such as systemic lupus erythematosus (SLE) and the antiphospholipid syndrome are associated with poor pregnancy outcome underscores the critical role of the maternal immune response (18). Abnormalities in fetal regulation of the maternal immune response, even...

Antiinsulin Receptor Antibody MA20

Autoimmunity usually entails aberrant recognition of self-antigens by antibodies, which leads to a variety of pathologies. Autoantibodies generated against human insulin receptor share an a subunit epitope with murine antibody MA20 (Zhang and Roth, 1991). Eleven rounds of RNA selection were completed against the

Monoclonal Antibody MAb to Acetylcholine Receptor

Myasthenia gravis is a neuromuscular disorder characterized by muscular weakness and fatigue resulting from antibody-mediated autoimmune response to acet-ylcholine receptors (AChR) (Willcox, 1993 Drachman 1994). Lee and Sullenger isolated 2'-amino-modified aptamers that bound to MAb198, a monoclonal antibody that recognizes the major immunogenic epitope on human AChR (Saedi et al., 1990 Lee and Sullenger, 1997). After 12 rounds of selection, a modified RNA aptamer was isolated that binds MAb128 with a Kd of 60 nmol L. The MAb128 aptamer was able to protect TE671 cells from antigenic downmodulation in a dose-dependent manner, with an ED50 of 5 mmol L and a maximum inhibition of 70 (Lee and Sullenger, 1997). Moreover, the aptamer could also protect AChR from autoantibodies found in patients with myasthenia gravis. A subsequent 2'-fluoropyrimidine-modified RNA selection was performed to generate an improved MAb128 aptamer that is even more effective at protecting AChR from the monoclonal...

Combined Hereditary Complement Deficiencies

Combined heterozygous C4 and C2 deficiency has been reported for 15 individuals from six families (72). About 30 of the people had SLE or another autoimmune disease. The C2 deficiencies were all due to the 28-bp deletion in the C2 gene, whereas 8 of the C4 deficiencies were all due to heterozygous C4A null alleles and five were due to C4B null alleles (the other two C4 deficiencies could not be identified as null alleles). From the frequencies of C2, C4A, and C4B deletions, the expected combined C2 and C4 deletion frequency of the population is 0.001.

Complement Component Deficiency In Systemic Lupus Erythematosus

At the time when the original hypothesis was formulated, the leading hypothesis on the etiology of SLE was that the disease was initiated by some yet unidentified viral agent. Hence, it was postulated that the early complement components were involved in specific host defenses to the putative viral agent. This hypothesis has not been totally excluded, but no viral etiologic agent has been identified in human SLE after 25 years of searching. A new major hypothesis on the etiology of SLE is that aberrant apoptosis leads to a breach of self-tolerance and autoimmunity. New evidence on the role of early complement components in clearance of apoptotic cells has lead to a new interesting hypothesis on how complement is involved in host defenses to lupus disease. The most widely accepted hypothesis is that these components are essential for clearance of immune complexes and since SLE disease is mediated by immune complexes, deficiencies of these components lead to disease. This hypothesis...

Nutrition And Dysphagia

Neurogenic dysphagia means dysfunction in the mechanisms that deliver a food or liquid bolus into the esophagus. Aspiration, respiratory compromise, malnutrition, and dehydration are the serious consequences. Indeed, dys-phagia is the potential cause of a pulmonary infection in any patient with stroke, TBI, motor neuron disease, cerebral palsy, MS, advanced Parkinson's disease, cervicomedullary pathologies such as a syrinx, the Guillain-Barre syndrome, myasthenia gravis, and most neuro-muscular diseases.

Complement Protein Knock Out Mice

The B6 1pr mouse develops minor autoimmune features. Introduction of CR1 CR2 deficiency into this mouse permits the development of intense autoimmune features (13). This observation indicates that complement receptors are important in the elimination of B-cells that display reactivity with self-antigens. This explanation assumes that self antigens initiate a strong B-cell signal which leads to cell death and the absence of the CR2-mediated enhancement of the signal permits their survival (14,15). When the complement receptor deficiency was introduced into the hen egg lysozyme (HEL) double transgenic mouse model for immune cell tolerance, the paucity of the production of anti-HEL antibodies was not reversed. It should be noted though that the numbers of the circulating B-cells increased and they responded normally to stimulation (16,17) indicating that there is some effect on B cell biology but not enough to break tolerance. These two sets of experiments suggest a relative role for CR2...

Epidemiology and Pathogenesis

Autoimmune diseases are chronic disabling disorders in which immune dysregulation leads the body to attack its own organs and tissues. More than 80 autoimmune diseases have been identified. The most common of these diseases include systemic lupus erythematosus (SLE), multiple sclerosis, type 1 diabetes, autoimmune thyroid diseases, myasthenia gravis, and rheumatoid arthritis (RA). Collectively, autoimmune diseases are thought to affect approximately 14-22 million people in the U.S. and represent a significant physical, emotional, social, and fiscal burden to the country's health care system. For reasons that are not clear, the prevalence of autoimmune diseases appears to be rising. Further, the development of effective therapies has lagged behind the growing prominence of these diseases. Immune complexes (IC) are integral to the pathogenesis of several autoimmune diseases, including SLE and RA. The prototypic experimental model of soluble IC disease, the Arthus reaction, has served as...

Summary and future considerations

It is clear that a better understanding of our immune system and the way it can differentiate between self-antigens and non-self-antigens will have a huge impact on different areas of clinical medicine. Such developments could help treatment of patients with cancer, infection, autoimmune diseases and allergies, as well as those patients undergoing organ transplantation or requiring aggressive forms of chemo- or radiotherapy.

Neuromuscular Diseases Presenting to the Neurological Intensive Care Unit

Failure is lengthy (Table 26.1), although in practice the principal causes are Guillain-Barre syndrome and myasthenia gravis, a detailed account of which follows. It is not always easy to arrive quickly at a clinical diagnosis. Physical signs may be confusing or misleading. For instance, it is relatively common to have difficulty distinguishing an acute myelopathy from a rapid polyneuropathy, despite the clearcut distinctions described in textbooks. Acute myelopathies may present with areflexia and an absent spinal cord level and bladder dysfunction is occasionally seen in Guillain-Barre syndrome. Investigations are usually necessary and those to consider urgently are spinal cord imaging, a creatinine kinase and electrophysiology.

Extracellular Targets

The majority of aptamers with potential therapeutic utility selected to date target extracellular proteins. Extracellular therapeutic targets, such as growth and coagulation factors of the vasculature, have the advantage of ready access to aptamer intervention without need for enabling aptamer access to cells or tissue spaces. Broad therapeutic areas are represented among aptamers directed against extracellular targets, including angiogenesis oncology (Green et al., 1995, 1996 Nobile et al., 1998 Ruckman et al., 1998 Lupold et al., 2002 Chen et al., 2003 White et al., 2003), inflammation (Wiegand et al., 1996 Rhodes et al., 2000, 2001), anticoagulation and thrombosis (Bock et al., 1992 Gal et al., 1998 Rusconi et al., 2004 Rusconi et al., 2000, 2002 Tasset et al., 1997), and autoimmune disease (Tsai and Keene, 1993 Doudna et al., 1995 Lee and Sullenger, 1997 Kim et al., 2003). The aptamer drug Macugen (pegaptanib) (Ruckman et al., 1998 Eyetech Study Group, 2002, 2003), which is...

Chronic Inflammatory Demyelinating Polyradiculoneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), also known as chronic relapsing polyneuropathy, is an immune-mediated inflammatory neuropathy. It is a rare autoimmune disorder in which there is a swelling of nerve roots and destruction of the myelin sheath over the nerves. Histologically, the damaged nerve has a well-developed onion bulb-like morphology.7 Clinically, CIDP is characterized by slowly progressive weakness and sensory loss involving the legs and arms. Although it can occur at any age and in both sexes, CIDP is more common in young adult males. Symptoms include tingling or numbness beginning in the toes and fingers, weakness of the arms and legs, aching pain in the involved muscles, loss of deep tendon reflexes, fatigue, and abnormal sensations.14 To diagnose CIDP, a peripheral nerve biopsy is sometimes performed. Treatment consists of a course of intravenous immunoglobulin (IV Ig), plasmapheresis, or a corticosteroid such as prednisone, which is typical...

Primary Insufficiency

Autoimmune adrenalitis is the most common form of adrenal insufficiency, accounting for two thirds or more of primary adrenal failure cases. Association of Addison's disease with other autoimmune diseases is common. In 1981, Neufeld and coworkers proposed a classification system for these polyglandular autoimmune (PGA) syndromes that divided those associated with Addison's disease into type I and type II.5 Patients with PGA-I syndrome have hypoparathyroidism, chronic mucocutaneous candidiasis, or both, as well as infrequent other autoimmune diseases associated with their

Giant Cell Arteritis Temporal Arteritis

Temporal arteritis is a systemic autoimmune disorder. Pathologically, there is a granulomatous inflammation of large and medium-sized arteries. It generally occurs in patients older than 55 years, with no gender predilection. Involvement may occur in any organ system. Ocular involvement is generally associated with inflammation of the posterior ciliary arteries. General symptoms include amaurosis fugax, headaches, scalp tenderness, jaw claudication, occasional ear pain or arthralgias, pain and tenderness on one or both temples, malaise, and intermittent fevers. Ocular symptoms include loss of vision, diplopia, pain, red eye, and ocular-ischemic syndrome. The workup of patients suspected to have giant cell arteritis includes a careful history of nonvisual symptoms, examination, and laboratory studies to include erythrocyte sedimentation rate (ESR), C-reactive protein, and complete blood count with differential. Using the Westergren method, the value for a normal ESR is 30 mm hr for a...

Vasculitis Associated with Antiphospholipid Antibodies

Antiphospholipid antibodies (aPL) are a heterogenous family of antibodies of the IgG, IgM, or mixed classes with varying cross- reactivities. Antibodies within this family include anticardiolipin antibodies, antibodies responsible for the false- positive Venereal Disease Research Laboratory (VDRL) serology and the lupus anticoagulant. Antiphospholipid antibodies may be detected in a number of clinical settings. Normal elderly may have aPL of unclear significance. They may be seen in patients treated with phenothiazines, antiarrhythmics, and anticonvulsants, or in the context of infections or malignancy. Antiphospholipid antibodies are commonly seen in patients with systemic autoimmune disorders such as systemic lupus erythematosus. The primary antiphospholipid antibody syndrome comprises recurrent venous or arterial thrombosis, fetal loss, thrombocytopenia and positive results on serological tests for lupus anticoagulant or anticardiolipid antibodies....

Systemic Lupus Erythematosus

Additional investigation of mechanisms involved in the generation of SLE-induced organ damage will serve to direct future therapies. Of relevance to SLE and other autoimmune diseases are therapies that may eliminate specific autoantibodies involved in the pathogenesis of the disease such as anti-idiotype antibodies and sensitization of T cells against specific autoantibodies.

Concluding Remarks

Three decades ago the role of complement in human disease was largely unknown. Two decades ago it became evident that complement activation was associated with a number of pathophysiologic conditions, although the role of this activation in the pathogenesis of the diseases was largely unknown. During the last decade studies using specific complement inhibitors or complement knock-out animals have revealed that complement plays a crucial role in the pathogenesis of tissue inflammation in a number of animal disease models. These include local and remote damage after ischemia and reperfusion, immune-complex and autoimmune diseases in general and joint, kidney and central nervous system diseases in particular, ARDS and systemic inflammatory response due to sepsis or extracorporeal circulation, antibody-mediated fetal loss, and allo- and xenotransplantat graft rejections. Based on these encouraging data a great enthusiasm evolved for treatment of human diseases using complement inhibitors....

Cholinesterase Inhibitors

Side effects of cholinesterase inhibitors result from overstimulation of the cholinergic system at the level of the muscarinic receptors of the smooth muscle, the nicotinic receptors of the skeletal muscle, the autonomic glands, and the CNS. Signs of cholinergic excess include nausea, abdominal cramps, excessive secretions, and bronchospasm. This syndrome is distinct from myasthenia gravis and is usually diagnosed accurately. However, because overstimulation can lead to subsequent depolarization blockade and enhanced weakness, exacerbation of myasthenia and cholinergic crisis can be dangerously confused. In situations in which there is a question of too much or too little cholinesterase inhibition, edrophonium (Tensilon) given in 1-mg increments may be helpful. More likely, however, admission to an intensive care unit for transient cessation of cholinesterase inhibition is needed to elucidate whether the dose should be raised or lowered. It has been suggested that chronic...

Rehabilitative Interventions

Heat sensitivity is especially prominent, although muscle fatigue and lassitude can follow heat exposure in any patient with a neurologic disease, especially with stroke, myelopathies, or myasthenia gravis. Visual impairment from an optic neuritis may require magnifying lenses or braille materials. Diplopia sometimes responds to a prism, but patients more often prefer to cover one of their eyes, unless the resulting loss of depth perception is disabling. Pendular nystagmus causing oscil-lopsia often interferes with ADLs, vision, and balance. It has been successfuly reduced with isoniazid in some cases.109 An action tremor may also respond to up to 1200 mg of isoniazid or to propanolol, acetazolamide, glutethemide, benzodiazepines, or mysoline, although functional gains are generally modest. Deep brain electrical stimulation lessens tremor in some instances. Limb ataxia can be dampened by slightly weighting the distal limb or the utensils used by the patient....

Etiology and Epidemiology

Pancreatectomy Pancreatitis from many causes Viral infections Coxsackie viruses, measles Beta cytotoxic drugs Diabetogenic hormones (exogenous or endogenous) Growth hormone Epinephrine ACTH or glucocorticoids Hemochromatosis Disorders of insulin receptors Factors of immunity and autoimmunity Human leukocyte antigens (HLA)

Sjogrens disease chronic urticaria

Few well-controlled studies of androgen therapy have been reported in other rheumatological disorders. This is not just due to paucity of cases in the female-preponderant autoimmune diseases as there are no controlled studies of androgen therapy even in ankylosing spondylitis or gout, the male preponderant rheumato-logical diseases.

Mecanism Of Centripetal Lipid Accumulation Supraclavicular Fat And Face

Hypocortisolemia can be primary, in which there is a defect intrinsic to the adrenal gland, or secondary, when pituitary or hypothalamic dysfunction causes decreased secretion of CRH or ACTH. Primary adrenal insufficiency was described by Thomas Addison in 1855 and is most commonly associated with destruction of the adrenal glands, either by tuberculosis, acquired immunodeficiency syndrome (AIDS), autoimmune disorder, adrenal hemorrhage, or tumor. In such cases, ACTH levels are high in response to the low plasma levels of gluco-corticoids. Secondary adrenal insufficiency is most often caused by suppression of the hypothalamic-pituitary axis by exogenous glucocorticoid therapy. Endogenous causes are a result of pituitary destruction by large tumors, apoplexy (hemorrhage into a pituitary adenoma), pituitary infarction (Sheehan's syndrome), inflammatory process (lymphocytic hypophysitis, Langerhans cell histiocytosis), or granulomatous disease (sarcoidosis). In almost all cases, loss of...

Chronic Progressive External Ophthalmoplegia and Kearns Sayre Syndrome

Conditions to exclude include other mitochondrial diseases, primarily MERRF and MELAS any disease causing ophthalmoplegia when that is the sole presenting symptom, especially myasthenia gravis other diseases that cause multisystem involvement, such as collagen vascular diseases, particularly systemic lupus erythematosus and in the appropriate setting, Lyme disease (caused by infection with Borrelia burgdorferi) or Whipple's disease. The ultimate diagnosis is made by muscle biopsy and mtDNA analysis. There is no proven specific treatment, although coenzyme Q10 and carnitine have been used. Implanted cardiac pacemakers can be used for conduction defects. Associated endocrine abnormalities--growth hormone deficiency, diabetes mellitus, or hypoparathyroidism--can be treated medically. Although these conditions are considered chronic, complete heart block may result in sudden death.

Chronic Kidney Disease

Mehran Score

Several clinical factors are useful in identifying individuals at increased risk for CKD. Estimates of the incidence and prevalence of CKD indicate that 20 million people are currently affected in the United States,21 with diabetes mellitus and hypertension accounting for as much as 70 of the disease burden in this country. Additional clinical factors associated with CKD include autoimmune diseases, systemic infections, urinary stones, lower urinary tract obstruction, reduction in kidney mass, exposure to certain drugs such as NSAIDs, recovery from acute kidney failure, and a family history of kidney disease. Several sociodemographic factors are also useful in identifying individuals at increased risk for CKD. Ethnic minority populations, including African Americans, Native Americans, and Hispanic Americans, bear a disproportionate burden of advanced CKD22 and are more likely to develop ESRD than are whites.23 Such disparities also may result, in part, from differences in education,...

Tumors of Salivary Gland Lymph Nodes

Waldeyer Ring Pathology

Hepatitis C is also associated with MALT lymphomas of the salivary glands. In a series of 33 cases of primary salivary MALT lymphomas, 15 patients had a history of Sjogren's syndrome (45.5 ), 2 (6 ) other autoimmune disease, and 7 (21 ) hepatitis C infection (Ambrossetti, Zanotti, and Passaro et al. 2004). There is an increase in lymphoma in AIDS, however, although in 51 of patients in a study of 100 patients who died with AIDS without salivary gland symptoms who Not all primary salivary lymphomas fall into the MALT group, and follicular lymphomas comprise 30 and 22 of two recently published series (Kojima, Nakamura, and Ichimura et al. 2001 Nakamura, Ichimura, and Sato et al. 2006) (Figure 11.12). These lymphomas have a younger age of onset than MALT lymphomas, do not occur in patients with autoimmune disease, and appear relatively more common in the submandibular gland.

Guillain Barre Syndrome

The etiology of Guillain-Barre syndrome is unknown, but increasing evidence suggests it is probably a humoral and cellular autoimmune disease induced by infection with a variety of microorganisms. The background rate of Guillain-Barre syndrome is one to two cases per 100,000 persons annually. Guillain-Barre syndrome has been associated with several vaccines. An influenza vaccine used in the mid-1970s (swine flu

Table 556 Peripheral Neurotoxicity Of Antibiotics

A potentially fatal neurotoxic effect of all aminoglycosides is neuromuscular blockade, due in part to a curare-like effect of the aminoglycosides and also to a competition with calcium by these antibiotics. This side effect is related to dose and serum level. Aminoglycosides are relatively contraindicated in both presynaptic (e.g., botulism) and postsynaptic (e.g., myasthenia gravis) disorders of neuromuscular transmission. y They may further potentiate ether and other drugs used to induce muscular relaxation during anesthesia. Neomycin and netilmicin are the most toxic, and tobramycin and kanamycin are the least toxic. Sudden or prolonged respiratory paralysis due to aminoglycosides may be reversed by calcium infusion, cholinesterase inhibitors, and aminopyridines. y Erythromycin interacts with carbamazepine, causing carbamazepine levels to increase rapidly when erythromycin is introduced. Careful monitoring of the carbamazepine blood level and clinical symptoms of toxicity should...

Thromboangiitis Obliterans Buergers Syndrome

Differential diagnoses include other vasculopathies and autoimmune diseases such as systemic lupus erythematosus, scleroderma, polyarteritis nodosa, antiphospholipid antibody syndrome, GCA or TA. Other conditions such as pseudoxanthoma elasticum and Ehlers-Danlos may be considered as well. It is important to exclude proximal sources of emboli and atherosclerosis. y

Parotid Gland Tumour Mri Radiology

Scan Mono Lymph Nodes

Pathologic states of the salivary glands include tumors (epithelial and non-epithelial), infections and inflammation, autoimmune diseases, vascular lesion, and non-salivary tumors. secondary to edema. Both CT and MRI may demonstrate enhancement and enlargement of the parotid (or sublingual) duct. US shows slight decrease in echogenicity relative to normal. These patterns are not unique to bacterial or viral infection or inflammation and may be seen with autoimmune diseases such as Sjogren's syndrome or a diffusely infiltrating mass. The surrounding subcutaneous fat also demonstrates heterogenous increased density from edema resulting in a dirty fat appearance. There is also thickening of fascia and the platysma muscle (Bialek, Jakubowski, and Zajkowski et al. 2006 Madani and Beale 2006a Shah 2002). The etiology of chronic inflammatory states of the salivary glands varies by the particular gland in question. Chronic inflammatory changes in the parotid gland tend to be related to...

Complement and FcyR in experimental models of ICmediated disease

Although the Arthus reaction has long been used to model human IC-mediated autoimmune disease, the question arises as to whether the immune mechanisms mediating inflammation in the Arthus reaction mirror the mechanisms important in human disease. As shown in two models of RA and SLE nephritis that comprise many clinical features of the human diseases, this is likely the case. prevention is also achieved by deficiency of C5 or C5aR, or by anti-C5 antibody treatment. This illustrates that adaptive autoimmunity can induce inflammation that, in the effector phase, uses similar mechanisms to that identified by passive Arthus reaction models. in FcyRIIB' mice that display enhanced susceptibility in the Arthus reaction (131), collagen-induced arthritis (132) and Goodpasture's syndrome (133). The observation that ligation of FcyRIIB impairs signal transduction by chemoattractant GPCR (C5aR, CXCR2) provides a regulatory link between cellular (FcyR) and humoral (complement) immunity and adds a...

Evaluation Guidelines Table156

Edrophonium chloride (Tensilon), a short- acting cholinesterase inhibitor, is used in the diagnosis of myasthenia gravis (Tensilon test). As explained earlier in the discussion of fatigability, a symptomatic muscle that is most amenable to semiquantitative testing is chosen for the measurement of fatigability before and after the intravenous injection of edrophonium. This test is sometimes done in conjunction with injection of a saline placebo. However, because muscarinic as well as nicotinic receptors are stimulated by the accumulation of acetylcholine in the synaptic cleft, this test is difficult to perform in a blinded fashion because intestinal cramping and muscle fasciculations in the eyelids are generally produced by the edrophonium. The muscarinic effects may also cause a bradycardia that is sufficiently severe to induce fainting, and rarely asystole occurs in what appears to be an idiosyncratic reaction. Therefore, a small test dose of 0.2 ml is given first to...

Epidemiology and etiology

T1DM is an autoimmune disease in which insulin-producing -cells in the pancreas are destroyed, leaving the individual insulin-deficient. This is usually precipitated through genetic susceptibility and or an environmental trigger. Certain genetic markers can be measured to determine if a person is at risk of diabetes. The presence of human leukocyte antigens (HLAs), especially HLA-DR, is strongly associated with the development of T1DM. Over 95 of people with T1DM have HLA-DR3 and HLA-DR4 present. In addition, these individuals often develop islet cell antibodies, insulin autoantibodies, or glutamic acid decarboxylase autoantibodies. More than 90 of persons with T1DM have at least one diabetes-related antibody present. As more -cells are destroyed, glucose metabolism becomes compromised due to reduced insulin release following a glucose load. At the time of diagnosis, most patients have a 90 loss of -cell function. The remaining 10 of -cell function at diagnosis creates a honeymoon...

Copper Silver and Gold

Toxic Groups Drug Design

The human variant of the antioxidant enzyme, superoxide dismutase, contains both copper and zinc (Figure 10.14). The toxic superoxide anion, O-, is sometimes deliberately produced by organisms for particular objectives. Thus, some phagocytes, which are part of the immune system in higher organisms, produce large quantities of superoxide together with peroxide and hypochlorite by means of oxidases in order to kill invading microorganisms. In unfortunate cases this protection system may fail giving rise to certain autoimmune diseases like rheumatoid arthritis. Under these circumstances, the superoxide dismutase enzyme is administered as an anti-inflammatory pharmaceutical. The same therapy is consistently applied during open heart surgery in order to protect the tissue against oxidative attack by the superoxide radical.

Vinyl chloride exposure and health effects

The mechanisms of toxicity for non-cancer VCM effects are not completely elucidated. VCM disease exhibits many characteristics of autoimmune diseases (e.g. Raynaud's phenomenon and scleroderma). B-cell proliferation, hyperimmunoglobulinemia, and complement activation, with increased circulating immune complexes or cryoglobulinemia indicating stimulation of immune response, have been observed. Postulated mechanisms for the non-cancer effects include

Dermatomyositis and Polymyositis

Dermatomyositis (DM) and polymyositis (PM) have been thought to have an autoimmune origin for many years. This concept is based on indirect associations with other autoimmune disorders, mononuclear inflammatory cells in affected muscles, and responsiveness to immunosuppressive agents. Genetic factors play a role, as evidenced by reports of identical twins with DM, families with other connective tissue diseases and DM or PM, and increased associations with HLA-DR3. Without convincing evidence of support, it has been hypothesized that these inflammatory myositides are the result of a viral infection. A number of other related conditions may have myositis as a feature and are considered to be overlap syndromes when the diagnostic criteria for both conditions are fulfilled. These are other autoimmune diseases such as PSS, SS, SLE, RA, and MCTD.

Management of Guillain Barre Syndrome on the Intensive Care Unit

Myasthenia Gravis In 1893, Jolly described a disease which he termed 'myasthenia gravis pseudoparalytica', pointing out that weakness increased with exercise and decreased with rest and that physostigmine might be an appropriate treatment.47 Then in 1936, the therapeutic effect of thymectomy was noted.48 Since then, there has been an outpouring of immunological studies on myasthenia gravis and its experimental counterparts, as it has become a prototypical organ-specific autoimmune disease. Despite this, the pathogenic link between thymic hyperplasia and the disease process remains mysterious. Myasthenia gravis is an autoimmune disorder in which antibodies are directed against the acetylcholine receptor antibodies of the neuromuscular junction. The prevalence of 1-10 per 100 000 is made up of two broad populations one mainly women in their 20s and 30s and one predominantly men aged between 50 and 70. A thymoma may occur in association with myasthenia gravis at any age it is an absolute...

Episodic Weakness Syndrome

And recovery after rest the patient with myasthenia gravis may complain of episodic weakness. Myasthenia gravis is seldom confused with these other disorders because of the features mentioned earlier and the predilection of the weakness for the ocular and cranial muscles. An episodic hemiparesis is more apt to lead to confusion. The most common cause of this is transient ischemic attack but the potential for confusion is greater with partial motor seizures or hemiplegic migraine. These entities can be differentiated clinically by paying careful attention to the mode of onset and the course of the weakness. Transient ischemic attack produces an abrupt and simultaneous onset of weakness in all the muscles that will be affected during the attack. A partial motor seizure may become manifest as an inhibition of motor function, producing a stepwise progression of weakness from one body part to the next (march) over many seconds to a few minutes as the wave of excitation or inhibition...

Neurologic and Neuromuscular Diseases

Data collected over several years suggest that MAC plays an important role in the loss of acetylcholine receptor at the neuromuscular junction in patients with myasthenia gravis (MG). This was initially suspected following the observation that C9 was deposited at the motor end-plate of the MG muscle fibres (Sahashi, 1980). The contribution of MAC to the ultrastructural damage in the postsynaptic membrane of myastenic muscle was further supported by the finding that an experimental model of MG could not be established in C5 deficient mice (Christadoss, 1988) and that treatment of rats with antibodies to C6 prevented the occurrence of the acute manifestation of the disease (Biesecker, 1989). The involvement of C in the induction of experimental model of myasthenia gravis is also proved by the recent finding of Lin and co-workers (2002) who showed that Daf1(- -) mice were more susceptible to antibody-mediated experimental MG than control Daf1(+ +) mice. We have been able to induce...

Future Prospects for Aptamer Therapeutics

Brenner, T., Hamra-Amitay, Y., Evron, T., Boneva, N., Seidman, S., Soreq, H. (2003). The role of readthrough acetylcholinester-ase in the pathophysiology of myasthenia gravis. FASEB J 17, 214-222. Drachman, D. B. (1994). Myasthenia gravis. N Engl J Med 330, 1797-1810. Hwang, B., Han, K., Lee, S. W. (2003). Prevention of passively transferred experimental autoimmune myasthenia gravis by an in vitro selected RNA aptamer. FEBS Lett 548, 85-89.

Hashimotos Thyroiditis

Hashimoto's thyroiditis, known as an autoimmune or chronic lymphocytic thyroiditis, is the leading cause of hypothyroidism. The pathogenesis of hypothyroidism is complex. Three mechanisms have been proposed (1) thyroid cell damage by the thyroid antibody-mediated complement attachment (2) T-cell-mediated cytotoxicity and (3) enhanced apoptosis (programmed cell death). The initial event is the formation of antibody in response to self-antigen such as thyroid peroxidase (TPO) and thyroglobulin this event does not normally happen. If self-antigen is falsely recognized by the immune system, antibody formation takes place to the specific self-antigen, creating organ-specific autoimmunity. This leads to immune complex deposition in the basement membrane of follicular cells and complement activation, as suggested in 1977.9 Weetman and associates confirmed the presence of terminal complement complexes around thyroid follicles.10 Thyrocytes attacked by complement through antibodies were shown...

Neuromuscular Junction Syndromes

MYASTHENIA GRAVIS The defect in neuromuscular transmission in myasthenia gravis (see Chapter50 ) produces a pure muscular weakness without the atrophy, fasciculations, or reflex changes seen in motor neuron disease. Myasthenia gravis also causes a pattern of weakness in the ocular and cranial muscles that is different from that seen in amyotrophic lateral sclerosis. A weakness of the extraocular muscles and eyelids producing diplopia and ptosis is common in patients with myasthenia gravis but rare in those with amyotrophic lateral sclerosis (see TableJ.,5,-2 ). Facial weakness is also common in myasthenia gravis, and the combination of ptosis and weakness of eye closure may be duplicated only by an acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome), which has a very different temporal profile. The other characteristic feature of myasthenia gravis is fatigability. The myasthenic muscle rapidly weakens with continued or repetitive use. The physiological...

Relationship Between Cytokines and Seminal Parameters

n spite of multiple in vivo studies, the involvement of cytokines and other immunoregulatory factors in male infertility is still unclear. The same cytokines that act as testicular immunomodulatory elements and regulate the physiological function of the male gonad appear in large concentrations in the semen in a number of pathological conditions, including autoimmune diseases 89, 90 , spinal cord injury 91 , varicocele 92 , or genital tract infection inflammation 93, 94 . Most investigators suggest that the cytokines detected in seminal plasma are associated with the incidence of leukocytospermia but are not the cause of semen abnormalities 51, 95 . The production of ROS by leukocytes or damaged spermatozoa may be one of the mechanisms by which cellular and humoral immunity could be triggered 96 . Leukocytospermia impairs sperm function by reducing semen antioxi-dant activity and causing enhanced T helper 1 switch 96 . Moreover, beneficial effects of supplemented vitamin E on...

Clinicopathologic Correlations

Superior Vena Cava Thrombosis

Although iodine deficiency is still a worldwide cause of thyroid enlargement, other important causes of goiter are infection, autoimmune disease, cancer, and isolated nodules. An enlarged thyroid may be associated with hyperthyroidism, hypothyroidism, or a simple or multinodular goiter of normal function.

Sleep Disordered Breathing and Neuromuscular Diseases

Breathing disturbances in neuromuscular diseases are due to weakness of respiratory muscles or upper airway muscles, or both. Respiratory muscle weakness is usually severe in Duchenne's muscular dystrophy and also occurs in myotonic dystrophy, limb-girdle dystrophy, polymyositis, poliomyelitis, amyotrophic lateral sclerosis, myasthenia gravis, and congenital myopathies.

Eosinophilic Myositis and Related Syndromes

Eosinophilia-myalgia syndrome (EMS) is a more recently described condition. A number of patients developed peripheral eosinophilia, fatigue, and myalgia associated with the chronic ingestion of L-tryptophan. Biopsies demonstrate inflammatory infiltrates of small and medium-sized vessels and connective tissues consisting of various cell types (histiocytes, CD4 + and CD8+ lymphocytes, and mast cells) but few if any eosinophils.' An autoimmune disorder or idiosyncratic response is suspected.' Since the withdrawal of L-tryptophan from the market, the number of cases reported has dramatically dropped. '122 It is likely that the vehicle, not L-tryptophan, was the responsible agent. The toxic oil syndrome, which was the result of a toxic contaminant in the production of rapeseed oil in Spain, is nearly an identical syndrome with identical pathology as EMS. '121

Lung Manifestations of Autoimmune Connective Tissue Disorders and Other Systemic Diseases

Other autoimmune diseases with pulmonary manifestations include mixed connective tissue disease (MCTD), Sjogren's syndrome, and progressive systemic sclerosis (scleroderma). Progressive systemic sclerosis can manifest with thickening and tightening of the skin of distal extremities, sclerodactyly, Raynaud's phenomenon, and multiorgan involvement of lungs, skin, kidney, heart, and gastrointestinal tract. Sixty percent of patients have shortness of breath others have cough, pleuritic chest pain, or hemoptysis. Lung CT scan in progressive systemic sclerosis and other autoimmune conditions can show pleural scarring and ILD, especially a ground-glass fibronodular pattern and honeycombing.

Hereditary C4 Deficiency

One large family of 35 individuals from three generations in Iceland with C4A null alleles has been reported (42). HLA typing and C4 allele typing was done by agarose-immunofixation techniques. Five of the family members had four or more criteria for SLE and an additional five members had clinical or laboratory evidence of SLE but did not fulfil four American College of Rheumatology (ACR) criteria. No other autoimmune diseases were seen in the family. The C4A null allele was highly associated with SLE in this family in that 9 of the 10 members with symptoms were C4A deficient. Interestingly, five different C4A null haplotypes were involved, including three that originated from non-consanguineous spouses.

Etiology and Immunology

The overwhelming evidence is that myasthenia gravis is due to an immune system dysfunction that produces an autodirected antibody against the acetylcholine receptor in the postsynaptic membrane of the neuromuscular junction. The evidence is clinical, laboratory, serologic, and therapeutic. The clinical evidence that myasthenia is an autoimmune disease is based on the association of myasthenia with vaccination, insect sting, infection, or trauma and its association with autoimmune diseases such as hypothyroidism, systemic lupus, and polymyositis. Many laboratory abnormalities point to the immune system dysfunction in myasthenia gravis. These include serologic abnormalities, increased incidence of a specific human leukocyte antigen (HLA-B8) in certain types of disease, histologic abnormalities of thymus and skeletal muscle, and abnormal responsiveness of lymphocytes to mitogens. Antinuclear antibodies are positive in uncomplicated myasthenia in about 18 percent of cases and in 54...

Hypersensitivity Reactions

Through complement-mediated lysis or antibody-dependent cytotoxicity. Type II reactions include haemolytic disease of the newborn, and autoimmune diseases such as Goodpasture's syndrome and myasthenia gravis. Type III reactions are mediated by formation of antigen-antibody or immune complexes and subsequent complement activation. Deposition of immune complexes near the site of antigen entry causes release of lytic enzymes by accumulated neutrophils and results in localized tissue damage. The formation of circulating immune complexes is involved in several conditions, including allergies to penicillin, infectious diseases such as hepatitis and autoimmune diseases such as rheumatoid arthritis.

Canine hip dysplasia a multifactorial problem

Unfortunately, some serious disorders are not caused by a single gene or even a combination of genetic effects (poly-genic). There may be an environmental factor predisposing animals to a disease, i.e. the disease is multifactorial. One of these diseases is canine hip dysplasia. Others include epilepsy, autoimmune diseases, heart disease and some forms of cancer.

Therapeutic Control Of

Neutralizig monoclonal antibodies (mAb) to late C components appear to be more promising as therapeutic agents and so far mAbs to C5 have proved to be effective in vivo in preventing the onset and progression of collagen-induced arthritis (Wang, 1995), in ameliorating the glomerulonephritis in lupus prone mice (Wang, 1996), in reducing the size of infarct areas and the degree of apoptosis following myocardial ischemia and reperfusion (Vakeva, 1998), and in preventing hyperacute rejection of xenotranplanted organs (Wang, 1999). A humanized scFv anti-human C5 now available for clinical trials has been found to attenuate myocardial damage, cognitive deficits and blood loss in patents undergong ardiopulmonary bypass (Fitch, 1999) and is now being tested in chronic inflammatory diseases including rheumatoid arthritis, glomerulonephritis and other autoimmune diseases together with another variant form (Kaplan, 2002).

The Lectin Pathway in Health and Disease

Several reports have presented evidence about the contribution of MBL deficiency in autoimmune diseases. In a number of studies involving patients with systemic lupus erythematosus (SLE), a higher incidence of MBL deficient subjects was documented than in the control groups (Davies et al., 1995 Lau et al., 1996 Sullivan et al., 1996 Davies et al., 1997). The adverse effects of MBL mutations on the propagation of rheumatoid arthritis (RA) have also been recognized (Garred et al., 2000 Graudal et al., 1998 Graudal et al., 2000 Ip et al., 2000). In a study on 128 type I diabetes Japanese patients MBL deficiency has been suggested to be a minor risk factor for possessing the disease (Tsutsumi et al., 2003). In contrast to the above observations a study on Japanese patients failed to detect any significant correlation between mutant MBL alleles and the occurrence of SLE or RA (Horiuchi et al., 2000). Moreover, Garred and coworkers found that RA patients with normal MBL alleles are more...

Acquired Juvenile Hyperthyroidism

Acquired hyperthyroidism in childhood results primarily from Graves' disease, an autoimmune disorder that occurs most often in adolescent girls. Hyperthyroidism results from thyroid-stimulating antibodies that affect overproduction and secretion of thyroid hormones. Symptoms of Graves' disease include agitation, hyperactivity, poor memory, and poor concentration (Fisher and Grueters 2008). Treatment options for Graves' disease include anti-thyroid medications, radioiodine, and surgery (Glaser and Styne 2008).

Bone Marrow Transplantation

The principal advantage of using the patient's cells is that they will be histocompatible with (biologically match) those of the body. This method avoids having the immunologically active white cells made by the transplanted hematopoietic cells attempt to reject the rest of the patient's body. This phenomenon, called graft-versus-host disease, is functionally like an autoimmune disease, in which the immune system attacks the other organs. The closer the match between the human leukocyte antigens (HLAs) of the transplanted blood cells and the recipient's cells, the less likely is graft-versus-host disease (Krance 2008). Recent studies have found that cryopreserved (frozen) umbilical cord blood from matched unrelated donors contains sufficient numbers of hematopoietic stem cells for pediatric patients, and even for some adults (Barker 2007). Because cord blood does not require as close a match or the harvesting of marrow from a living donor, the use of umbilical cord blood is becoming...

Preconception Counseling

During pregnancy, maternal illness can adversely affect the fetus and lead to adverse neonatal outcomes. Maternal hypertension, preeclampsia, alcohol and tobacco use, illicit drug use, and autoimmune diseases can cause intrauterine growth restriction (IUGR) and preterm birth. Children born to women with diabetes mellitus or gestational diabetes are at risk for shoulder dystocia, operative delivery, hypoglycemia, and birth trauma (American College of Obstetricians and Gynecologists ACOG , 2005). Maternal hyperglycemia at delivery also puts the infant at risk for hypoglycemia. Poorly controlled maternal hypothyroidism and hyperthyroidism are associated with low birth weight (LBW) and preterm delivery (ACOG, 2005). Fetal alcohol syndrome is directly caused by maternal alcohol use and abuse, and other illicit drug use is associated with preterm birth, congenital abnormalities, neurobehavioral abnormalities, and neonatal drug withdrawal syndromes (ACOG, 2005). Box 22-1 lists the more...

Carbon Dioxide or Bicarbonate

Infections, leukemia, rheumatic and autoimmune disorders, neoplastic disorders, chemicals, trauma, endocrine and metabolic disorders, hematologic disorders, drugs Overwhelming bacterial infection, viral infection, drug reaction, ionizing radiation, hematopoietic diseases, hypersplenism, anaphylactic shock, cachexia, autoimmune disease

Role of Oxidative Stress and Inflammation in the Pathogenesis of BPH

May be decreased in symptomatic BPH tissues. Animal models provided evidence for the presence of unique T-cell subsets which may suppress autoimmunity in healthy Sprague-Dawley rats resistant to chronic nonbacterial prostatitis 109 . Based on the available scientific evidence, it is highly likely that age-dependent weakening of the immune system, coupled with modified hormonal secretion, leads to the deterioration of a postulated population of suppressor cells. This decline in T suppressor cells population, which actively suppresses the recognition of prostatic antigens, leads to gradual infiltration of the prostate by lymphocytes and subsequent cascade of events resulting in BPH 110 .

Cytokines and Spermatogenesis

Ovulation Immune

Testes are considered to be an immunoprivileged organ due to their tolerance of autoantigens secreted during sexual maturity by reproductive cells. This phenomenon supports spermatogenesis 6 . The mechanisms which protect testes against autoimmune diseases are immunological anatomical blood-testis barrier (BTB) which protects against the antigenic leakage out of germ cells to immunological, intraparenchymal cells and against the transition of antibodies from endothelium to the lumen of seminiferous tubules secretion of immunosuppressive factors by macrophages, the Sertoli, Leydig, and peritubular cells and a limited presence of activated T lymphocytes (particularly that of CD8+) and the presence of regulatory T lymphocytes. Maintenance of the balance between inflammation and immunoprivileged gonad belongs, among other, to the function of cytokines which perform both the roles as proinflammatory mediators and immunosuppressive ones 7 .

Cytokines and Oxidative Stress in the Germ Line

Abstract Cytokines are important mediators of the immunologic response and involved in numerous physiological and pathological processes in the male genital tract. The same cytokines that act as elements of immunomodulation for the male gonad appear in large concentrations in semen in a number of pathological conditions, including autoimmune diseases, spinal cord injury, varicocele, or genital tract infection inflammation. The activated macrophages and neutrophils release reactive oxygen intermediates and secrete proinflammatory cytokines, both of which can affect spermatozoa through peroxidative processes of sperm membrane components and DNA. Elucidation of these mechanisms and their interactions can be critical to develop novel diagnostic tests and treatment of male genital tract infection inflammation. This chapter covers the current evidence about a relationship among the cytokines, antioxidants, prooxidants, and semen parameters.

Neuromuscular blocking drugs and their antagonists

The neuromuscular junction in infants is not mature. Electrophysiological studies demonstrate that the response of the junction is similar to what one might observe in a patient with myasthenia gravis. In other words, the junction is very sensitive to the effects of neuromuscular blockers. These drugs are polar and as a result distribute mainly to the extracellular space. Because this space is larger in the infant, the dose of drug required to depress twitch tension is similar or slightly larger than that required for adults on a dose unit weight basis. The larger volume of distribution explains why drugs that depend on the kidneys or liver for elimination have a longer duration of action. Conversely, drugs such as atracurium which are degraded by a combination of ester hydrolysis and Hoffman elimination act for a shorter time because of the larger extracellular space.

Factors affecting duration of nondepolarizing neuromuscular block

In this disease, the number and half-life of the postsynaptic receptors are reduced by autoantibodies produced in the thymus gland. Thus, the patient is more sensitive to the effects of non-depolarizing muscle relaxants. Resistance to succinylcholine may be encountered.

Anticholinesterase drugs

Cholinesterase, thereby decreasing the breakdown of released ACh they exert both nicotinic and muscarinic effects. The action on the ANS tends to appear at low doses, as nicotinic effects are dose-related. They are used in anaesthesia to reverse the neuromuscular blockade of non-depolarizing muscle relaxants (see Ch. 19). Their other uses include the diagnosis and symptomatic management of myasthenia gravis, where pyridostigmine is a useful, relatively long-acting agent. Anticholinesterases are used occasionally for their muscarinic effects to increase gastrointestinal and bladder smooth muscle tone topical anticholinesterases are also used in ophthalmology' as miotic agents.

Anaesthesia For Strabismus Surgery

Squint and ptosis are presenting signs of the progressive external ophthalmoplegia syndrome (PEO). Patients with this syndrome may have marked cardiac and respiratory decompensation and pose a significant hazard for anaesthesia. Preoperative pulmonary function testing is advisable. Myasthenia gravis may also present with ptosis and strabismus.

Distribution and Incidence

The disease has a worldwide distribution and has been identified as the primary cause of death at the average annual rate of 1.5 per million in the United States. If cases coded as contributory or as a complication are included, then the total would be 2 to 2.5. This seems to be the safest method of reckoning the actual incidence of myasthenia gravis, and previous estimates of 1 in 1,600 of the population probably vastly overestimate the incidence of myasthenia. There is no difference between whites and non-whites, and there is no difference in nationality. The death rate is slightly higher for women than men. In age-adjusted death rates for all ages, there is no appreciable difference in nine geographic regions of the United States. Thus myasthenia gravis seems to be uniformly distributed throughout the United States, and probably is uniformly distributed throughout the world. There is no difference between city and country in the incidence of myasthenia gravis, and the age-specific...

Diagnosis and Pathology

Is unmistakable and is usually associated with bilateral ptosis, weakness of the face, and difficulty in smiling, chewing, and talking. The clinical diagnosis is confirmed by demonstrating electrical defects in transmission at the neuromuscular junction, responsiveness to anticholinesterase drugs, or the presence of the anti-acetylcholine receptor antibody circulating in the patient's blood. The consistent pathology found in every patient is autoimmune destruction of the postsynaptic receptor, simplification of the postsynaptic membrane, widening of the synaptic gap, and reduction in the acetylcholine receptor numbers and efficiency. Thymic pathology is also present in myasthenia gravis. Approximately 80 percent of patients have germinal centers and enlarged thymus, and about 10 percent of patients have a thymic tumor, a thymoma.

Clinical Manifestations

The single most important clinical feature of myasthenia gravis is weakness of skeletal muscle worsened by exercise and relieved by rest. Without this feature there can be no diagnosis. Weakness with easy fatigability is the only constant in this disease all other features are variable. For instance, the weakness is usually worse in the afternoon and evening, although some patients are weaker in the morning when they first awaken. Usually the muscles supplied by the cranial nerves are the first and most severely affected, with resultant diplopia, ophthalmoplegia, dysphagia, dysphonia, dyspnea, and dys-mimia. The disease may involve proximal lower- and upper-extremity muscles. In rare instances, however, proximal muscles weaken first. Involvement of individual muscles may be symmetrical, but is often asymmetrical with a dominant leg and arm usually weaker than a nondominant counterpart. Myasthenia gravis can also present as weakness of a single muscle - for example, the external rectus...

Neurological Examination

Several disorders of the motor system are associated with sleep alterations. Strength should be examined, specifically the strength of the neck and respiratory muscles. Patients with myopathies, neuropathies, and neuromuscular junction disease can have significant chest wall weakness. In acute or chronic demyelinating polyneuropathy (Guillain-Barre(c) syndrome), tendon reflexes are lost and there may be additional bulbar cranial nerve weakness. In patients with myasthenia gravis, initial inspiration and expiration volumes may be normal, but repeated testing demonstrates rapid fatigability and poor aeration. In the condition multiple system atrophy, a diffuse degenerative condition with numerous areas of the nervous system affected, typical signs include parkinsonism in the form of bradykinesia and rigidity and gait dysfunction, along with cerebellar dysfunction-like dysmetria, ataxia, or tremors. Spinocerebellar atrophies are also associated with sleep...

Progressive Systemic Sclerosis

Antinuclear antibodies are typically found, usually in a nucleolar pattern antibodies to Scl-70, a soluble nuclear antigen, are specific, though insensitive. The demonstration of antibodies to smooth muscle and cytotoxicity to cultured endothelial cells suggests that autoimmunity plays a role in pathogenesis. The etiology of PSS is unknown, but glandular inflammatory processes appear to be related to cell- mediated immunity or to antibody-mediated cytotoxicity rather than to immune complex deposition.' Immune complex disease appears to be responsible for rare cases of associated vasculitis.

Principles of Antiepileptic Drug Treatment

Skin eruptions represent the most commonly encountered idiosyncratic reaction associated with AEDs. Generally appearing within the first 3 months of treatment, rashes are usual benign, and they resolve with dosage reduction or discontinuation. Severe reactions including Stevens-Johnson syndrome, exfoliative dermatitis, and toxic epidermal neurolysis occur rarely. Antiepileptic drugs can produce megaloblastic anemia, leukopenia, thrombocytopenia, aplastic anemia, asymptomatic elevations of hepatic transaminases, and life-threatening hepatotoxicity. Chronic idiosyncratic reactions include disorders of connective tissue and nervous system, endocrinopathies, and autoimmune disease.

Partially Characterized Syndromes

A positive AChR antibody test excludes a congenital myasthenia, but because cases of AChR antibody-negative myasthenia gravis exist, a negative test is less helpful. A positive edrophonium (Tensilon) test confirms the presence of a myasthenic syndrome but does not differentiate congenital myasthenia from myasthenia gravis. It may be negative in some patients with congenital myasthenia in whom there is a deficiency of acetylcholinesterase. EMG studies may show a decrement in the compound muscle action potential to repetitive stimulation but at 10 Hz rather than the typical 3 Hz. Single-fiber EMG may show excess jitter and blocking. Morphological, immunostaining, and immunochemical techniques and in vitro neurophysiological tests on intercostal muscle containing motor end plates are research methods for confirming and characterizing the nature of a congenital myasthenia. y , y Genetic analysis may show, for example, mutations of genes encoding for subunits of AChR.y

Oculopharyngeal Muscular Dystrophy

Oculopharyngeal muscular dystrophy can be distinguished from inclusion body myositis, which presents as dysphagia. It also has rimmed vacuoles, but the filaments seen are larger and are present in the cytoplasm as well as the nucleus and there are no ocular palsies. Ocular myasthenia gravis without waxing and waning of symptoms may produce weakness in the same distribution as oculopharyngeal muscular dystrophy, but it generates demonstrable neuromuscular junction transmission defects on EMG and neuromuscular junction abnormalities on morphological studies. Although late onset of the mitochondrial myopathy, Kearns-Sayre syndrome, or oculocraniosomatic disease may present with ptosis, histochemical and ultrastructural studies of muscle show biochemical defects in the respiratory chain and mitochondrial DNA deletions.

Myopathic Syndromes

As is often the case in medicine, there are exceptions to these general rules. The distal muscles may be weaker than the proximal muscles (e.g., myotonic dystrophy, inclusion body myositis), or a motor neuron disorder may affect the proximal musculature more than the distal, mimicking a myopathy (Kugelberg-Welander syndrome). Some myopathies affect the cranial and ocular muscles rather than limb muscles, as in, for example, the chronic progressive external ophthalmoplegia (CPEO) syndrome. The abnormal eye movements can be differentiated from those in myasthenia gravis in CPEO eye movements are restricted symmetrically and diplopia is not a complaint, whereas in myasthenia gravis double vision is a common symptom.

Experimental Allergic Encephalomyelitis

As mentioned earlier, there is no spontaneous animal model that closely resembles MS. EAE is the most widely studied animal model of this disease. EAE is an antigen-specific, T-cell-mediated autoimmune disease that can be induced in many species, although rat and mice models predominate in the literature. Acute EAE is a monophasic illness that more closely resembles ADEM. Chronic-relapsing EAE closely mimics the clinical course of MS with repeated clinical relapses from which the animal makes an incomplete recovery some animals develop a slow progressive course after several relapses. Although there is considerable variability in the various EAE models, several closely parallel the pathological picture of MS with perivascular inflammation and primary demyelination initially and subsequent gliosis and axonal loss.

Congenital Myasthenias

The onset of myasthenic symptoms at birth or in patients with a family history of this disease has always made congenital forms of myasthenia a diagnostic possibility. With the advent of the acetylcholine receptor (AChR) and the calcium channel antibody test as markers for myasthenia gravis and Lambert Eaton myasthenia, it has become apparent that congenital myasthenia, like the congenital myopathies, may present later in life and, in some cases, without a family history.

Abnormal Findings and Clinical Uses of Repetitive Nerve Stimulation

Repetitive nerve stimulation is a useful technique for evaluating neuromuscular transmission. In diseases in which such transmission is impaired, the muscle response to repetitive nerve stimulation may show abnormal alterations in size or area. In myasthenia gravis, a progressive decrement in the response may occur with repetitive stimulation (especially at 2 to 3 Hz), or an initial decrement may be followed by a leveling off of the response at a reduced size. Abnormalities are more likely to be found in proximal rather than distal limb muscles and in facial rather than limb muscles. Normal findings do not exclude the diagnosis. By contrast, in patients with Lambert-Eaton myasthenic syndrome or botulism, the response to a single stimulus is abnormally small and stimulation at a slow rate leads to a further reduction in response size with rapid rates of stimulation, a progressive increase in size of the response occurs.

Evaluation Guidelines Table132

Disorders of speech and swallow suspected to be due to neuromuscular disorders such as motor neuron disease or myasthenia gravis may be evident on electrophysiological testing. Repetitive stimulation on nerve conduction studies, and single fiber assessment of jitter may aid in the diagnosis of myasthenia. Electromyography (EMG) of the tongue or limb muscles may demonstrate denervation indicative of motor neuron disease. The location of a nerve lesion producing vocal cord paralysis may be established by EMG testing of the thyroarytenoid Other Tests. Patients with voice disorders should undergo careful otolaryngological evaluation of the neck and pharynx, and visualization of the vocal cords by either indirect or direct laryngoscopy. Paresis of the left vocal cord may result from disease processes in the chest involving the recurrent laryngeal nerve, such as an expanding aortic aneurysm, mediastinal adenopathy, or lung neoplasm. Chest radiographs, and possibly CT,...

Overview

The adaptive response is based on the premise of distinguishing self from nonself. Its defining characteristic is the extreme degree of specificity of its response. A large pool of B and T lymphocytes, each with a receptor specific to a unique nonself antigen, continually circulates through the body and lymph system in a naive state awaiting exposure to the appropriate antigen. Activation of the adaptive immune response is primarily mediated through T cells (i.e., B-cell activation requires T-cell support) and requires two signals T-cell receptor binding to antigen presented on major histocompatibility complex (MHC) molecules and a co-stimulatory second signal. Two classes of MHC molecules exist. MHC I molecules are expressed on the surface of all nucleated cells and present pep-tides derived from the products of degradation of intracellular proteins to CD8+ T cells. MHC II molecules are expressed on the surface of antigen presenting cells (APCs), which process and present antigen...

Immune System

It soon became clear that delayed hypersensitivity could take the form of autoimmune disease, and that this kind of disease could often be reproduced by injecting material from the target organ in Freund's adjuvant. During the 1950s, laboratories in Britain and the United States worked on the problem using experimental allergic encephalitis as a model. Under the microscope, all the lesions looked very much the same There was always a cuff of cells surrounding the small blood vessels. Most of the cells were lymphocytes, with some phagocytic cells, the macrophages. The New York immunologist Sherwood Lawrence insisted that he was able to transfer specific sensitization with a cell-free extract from sensitized cells he called his putative agent transfer factor. Other immunologists thought that there was something wrong with his experiments. There were no known soluble factors, other than antibody, or perhaps antigen - Burnet thought it must be antigen -that could transfer a specific...

Epidemiology

In most GBM patients, no specific risk factors can be identified. Glioblastomas can occur in association with specific genetic disorders such as Li-Fraumeni syndrome or neurofi-bromatosis or as part of nonspecific familial aggregations, but this accounts for a minority of patients. Other factors, such as presence of allergies, asthma, or autoimmune diseases, may be somewhat protective.24 Numerous environmental exposures have been loosely associated with GBMs, including nitrates, pesticides, synthetic rubber, petrochemicals, polyvinyl chloride, and formaldehyde. However, the strengths of these associations are not compelling. Ionizing radiation can definitely predispose to GBM development, but this also accounts only for a small minority of GBM patients. Electromagnetic fields generated by power lines or cell phones have not been associated with GBMs to date.7

Reactive Protein

An acute-phase reactant glycoprotein, C-reactive protein (CRP) is associated with inflammation. CRP is one of the first proteins to become elevated after an inflammatory process has begun and disappears rapidly when inflammation subsides. In healthy persons, CRP levels are usually less than 0.8 mg L and are often below the detection limit for standard assays. Serum levels may increase dramatically to exceed 100 mg L in the presence of bacterial and viral infections, inflammation, severe trauma, surgery, neoplastic proliferation, tissue injury, or necrosis, and transplant rejection. Moderate elevations may be seen with myocardial infarction, autoimmune diseases, rheumatic fever, pregnancy, and postopera-tively, as well as in obese persons and women taking estrogen replacement therapy or with an intrauterine device in place. CRP is not affected by age, race, or food intake and does not have significant circadian variation. Drugs that may reduce or suppress CRP levels by controlling...

Clinical History

Precipitating elements Alcoholism, diabetes mellitus, autoimmune diseases, malignancy, hypertension, sarcoidosis, acute porphyria, hyperthyroidism, and pregnancy have been associated with facial palsy. In addition, many infectious diseases can cause CN VII palsy, such as tuberculosis, mononucleosis, poliomyelitis, syphilis, and human immunodeficiency virus. A recent ear infection, with or without otorrhea, is suspicious for an otological infection or cholesteatoma as the possible etiology. An upper respiratory infection commonly precedes Bell's palsy. Facial palsy has been seen after immunizations for polio and rabies and after exposure to toxins like arsenic, carbon monoxide, and ethylene glycol. A family history of facial nerve palsy is seen with Melkersson-Rosenthal syndrome and occasionally with Bell's palsy. Maternal infections (e.g., rubella), drugs used during pregnancy (e.g., thalidomide), and a difficult delivery, especially if forceps were used, have been associated with...

Muscle strength

Such methods of quantitating fatigability are especially important when one is assessing the patient's response to the acetylcholinesterase inhibitor edrophonium chloride (Tensilon) as a test for myasthenia gravis. For example, one may test how many squats can be performed before and after the injection of Tensilon. The muscles or movements to be tested depend to a great extent on the patient's symptoms, but whenever possible a movement should be chosen that can be quantitated as accurately as possible. Another quantifiable method is the length of time a posture can be held. For example, if the patient complains of ptosis or double vision, the length of time the patient can maintain upward vision before ptosis or diplopia occurs can be estimated. Another is the length of time a patient can hold the arms out before they fall below a horizontal 90 degrees. Sometimes the fatigability of the muscles involved in myasthenia gravis cannot be readily quantified. For example, weakness of the...

Malignant Lymphoma

Marginal zone lymphomas can involve the stomach, salivary gland, thyroid gland, dura, lung, skin, ocular regions, and breast.108 The stomach and thyroid gland are normally devoid of lymphoid tissue but acquire lymphoid tissue in response to chronic antigenic stimulation by chronic infections or autoimmunity that is, the stomach in response to infections with Helicobacter pylori and the thyroid gland to autoimmune thyroiditis.

Human Interferon g

The function of major histocompatibility complex (MHC) class I and II genes as well as intercellular adhesion molecule 1 (ICAM-1) are upregulated by interferon-g (IFN-g) in numerous cell types (Van Seventer et al., 1990). Secretion of IFN-g can result in inflammatory and autoimmune diseases. RNA selections using 2'-fluoropyrimidine-, 2'-aminopyrimidine-modified RNA and a mixture of the two modifications (2'-F 2'-NH2) were screened for aptamers that bound to and inhibited IFN-g (Kubik et al., 1997). One particular aptamer 2'-NH2-30 had a Kd of 2.7nmol L and inhibited IFN-g binding to its receptor on A549 human lung carcinoma cells with a Ki of 10nmol L. This aptamer also inhibited IFN-g-mediated induction of MHC class I antigen and ICAM-1 expression, exhibiting IC50 values of 700nmol L and 200nmol L respectively (Kubik et al., 1997).

Preterm Labor

Data proving that magnesium sulfate prolongs pregnancy are lacking. It is con-traindicated for use in women with myasthenia gravis, and serious complications such as maternal pulmonary edema and cardiac arrest have been reported.34 More benign side effects such as flushing, headache, and nausea often cause discontinuation of magnesium sulfate therapy.34

CR1 Deficiency

Patients with a wide variety of autoimmune diseases including SLE, rheumatoid arthritis, hydralazine-induced lupus, discoid lupus erythematosus, primary phospholipid syndrome, essential mixed cryoglobulinemia, primary biliary cirrhosis, ulcerative colitis, and on cells in the MRL lpr mouse SLE model. The decrease in receptor numbers has been correlated with disease activity and can be reversed on the red cells by the production of new red cells stimulated by erythropoietin in some patients.