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Acupuncture for the treatment of chronic painful peripheral diabetic neuropathy: a long-term study medicine 0829085 safe oxcarbazepine 150 mg. Consensus statement: Report and recommendations of the San Antonio conference on diabetic neuropathy pure keratin treatment purchase oxcarbazepine 300 mg line. American Diabetes Association: Standards of medical care in diabetes treatment viral meningitis purchase cheap oxcarbazepine, Diabetes Care 27 (Suppl 1) symptoms gallbladder problems generic 150mg oxcarbazepine, 15 - 35 6 ombrello glass treatment order oxcarbazepine 300mg fast delivery. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathy. Cigarette smoking and prevalence of microangiopathy in juvenileonset insulin-dependent diabetes mellitus. Diabetes Care 1978; 1,(3): 146-9 19 Diagnosis, Therapy and Follow-up of Diabetic Neuropathy Part 1 14. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study [published erratum appears in Neurology 1993 Nov; 43(11):2345]. Medial arterial calcification and its association with mortality and complications of diabetes. Die transkutane elektrische Nervenstimulation in der Therapie der symptomatischen somatosensorischendiabetischen Polyneuropathie. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 1999; 353,(9153): 617-22 20 Diagnosis, Therapy and Follow-up of Diabetic Neuropathy Part 1 30. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Symposiumsbericht der Arbeitsgemeinschaft ?Diabetes und Nervensystem?der Deutschen Diabetes-Gesellschaft. Normative values of vibratory perception in 530 children, juveniles and adults aged 3-79 years. The effect of gamma-linolenic acid on human diabetic peripheral neuropathy: a double-blind placebo-controlled trial. Diabetic peripheral neuropathy: amelioration of pain with transcutaneous electrostimulation. Two-year experience with continuous subcutaneous insulin infusion in relation to retinopathy and neuropathy. Exercise and diabetic Neuropathy: Implications for Exercise Participation and Prescriptionfor Patients with Insulin-Dependent and Non- Insulin-Dependent Diabetes Mellitus. Lancet 1998; 352,(9145): 1978- 81, 21 Diagnosis, Therapy and Follow-up of Diabetic Neuropathy Part 1 47. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. The independent contributions of diabetic neuropathy and vasculopathy in foot ulceration. Associations of hypertension and complications in non-insulin-dependent diabetes mellitus. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Efficacy and safety of mexiletine in the treatment of painful diabetic neuropathy. Diabetes Care 1997; 20, (10): 1594-7 22 Diagnosis, Therapy and Follow-up of Diabetic Neuropathy Part 1 65. Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. Diabetes mellitus and its degnerative complications: a prospective study of 4,400 patients observed between 1947 and 1973: Part 1. Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973: Part 2. Mortality and treatment side-effects during long-term intensified conventional insulin treatment in the Stockholm Diabetes Intervention Study. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Symptomatic treatment of peripheral diabetic neuropathy with carbamazepine (Tegretol): double blind crossover trial. Shearer A, Scullham P, Gordois A, Ogleski A, Predicted costs and outcomes from reduced vibration detection in people with diabetes in the U. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy. Diabetic Medicine 2003, 20: 88-98 23 Diagnosis, Therapy and Follow-up of Diabetic Neuropathy Part 1 82. Zur Amputationshaufigkeit von Diabetikern in Deutschland (Ergebnisse einer Erhebung in zwei Landkreisen). The Sidney Trial Authors, for the Sidney Trial study Group:The sensory symptoms of diabetic polyneuropathy are improved with  lipoic-acid. Diabetic peripheral neuropathy: effects of age, duration of diabetes, glycemic control, and vascular factors. Pain relief in diabetic neuropathy: the effectiveness of imipramine and related drugs. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Prevalence and clinical correlates of cardiovascular autonomic and peripheral 24 Diagnosis, Therapy and Follow-up of Diabetic Neuropathy Part 1 diabetic neuropathy in patients attending diabetes centers. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Ziegler D, Luft D: Clinical trials for drugs against diabetic neuropathy: can we combine scientific needs with clinical practicalities? Symptomatic manifestations can be differentiated from asymptomatic forms only with special function tests. A correlation between micro- and macroangiopathic complications and overweight in type 2 diabetic patients has been ascertained. A meta-analysis of 15 prospective studies from 1966 to 2000 showed a significantly increased relative risk of 3. Moreover, an autonomic cardiac dysfunction increases the death rate after myocardial infarction and presents an independent risk factor for an apoplexy [Vinik et al. Clinically, mostly a heterogeneous pattern of symptoms from different organ systems is observed, which can lead to misinterpretation and is associated with a reduced quality of life. In Table 3, the procedure for the diagnosis of autonomic diabetic neuropathies is presented. In Table 16 (page 59), the most important clinical manifestations of autonomic diabetic neuropathy and the possibilities for diagnosis are summarised. In the cardiovascular and other organ systems, an early diagnosis before the manifestation of clinical symptoms is possible (Table 1). The importance of early diagnosis is emphasised by the fact that myocardial ischaemia progresses asymptomatically (silently) in 6. Together they can lead to a complete absence of heart rate variability as a result of cardiac denervation. In cases of orthostatic hypotension, a distinct drop in systolic blood pressure accompanied by appropriate symptoms may 32 Diagnosis, Therapy and Follow-up of Diabetic Neuropathy Part 2 occur (nonsystemic dizziness, syncope), whereby there have been previous indications of a dysfunction in the cerebral autoregulation of the blood supply [Mankovsky et al. These tests, in principle, can be carried out with a conventional electrocardiograph, a stop watch and a blood pressure instrument [strength of recommendation A]. For advanced diagnosis, computer-assisted systems are available that fulfill the requirements for the measurement of R-R intervals including spectral and vector analyses. Changes in arterial baroreflex activity are frequently observed in diabetes mellitus and autonomic neuropathy. Medications: for example, tricyclic antidepressants, antiarrhythmic drugs, clonidine [Rothschild et al. The length of the inspiration phase is six seconds and the expiration phase, four seconds. For healthy patients, the shortest R-R interval occurs around the 15th heart beat (interindividual, 5th to 25th beat) after standing up. Consequently, as a test parameter, the maximum/minimum 30:15 ratio is defined as the longest R-R interval between beats 20 and 40 divided by the shortest R-R interval between beats 5 and 25 after standing up. The numerically exactly defined 30:15 ratio proposed by Ewing and Clarke (1982) cannot be recommended because of the physiological variability in the reflex response just described. Valsalva manoeuvre While sitting, the subject blows into a mouthpiece that is connected to a manometer. The R-R intervals are recorded during the manoeuvre and for 15 seconds afterwards. Due to the potential risk of causing retinal or vitreous haemorrhages, the Valsalva manoeuvre should not be performed on patients with proliferative retinopathy. Orthostatic response First, the blood pressure is taken twice within a minute while the patient is supine, then, immediately after standing up and, afterwards, every 30 seconds for three minutes. The systolic blood pressure change is defined as the difference between the last value before standing up and the lowest value after standing up. The standard limits for advanced diagnosis in two commonly used computer programmes are summarised in Tables 7a and 7b. The Valsalva manoeuvre can be regarded as a global test of parasympathetic and sympathetic function. L owernorm allim itsof age-dependentcardiovascularautonom ic functiontests(N euro-D iag,softwareprogram m e)in309 testsubjects(151m en,158wom en),ages18?77years. They are caused by a dysfunction of the neuronal control of motility, secretion, absorption and perception in the gastrointestinal tract and, in fact, are probably due to functional and structural injury to efferent and afferent fibres of the sympathetic and parasympathetic nervous systems, including the ganglia of the gastrointestinal tract [Bittinger et al. However, there is only a relatively weak connection between symptoms and gastric emptying [Horowitz et al. Gastric emptying in diabetic patients is not affected by a Helicobacter pylori infection [Jones et al.


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Aspirin increases the relative risk for gastrointestinal and extracranial bleeds by 54% medicine 44175 buy cheap oxcarbazepine on-line. Based on the absolute benefts and risks observed the Calvin et al analysis [29] medicine 4 you pharma pvt ltd purchase discount oxcarbazepine on-line, aspirin therapy for an average of 6 medications 44334 white oblong cheap 300 mg oxcarbazepine mastercard. In the primary prevention cohort (2 medicine youth lyrics effective 600 mg oxcarbazepine,289 of the 15 treatment urinary tract infection purchase oxcarbazepine 600mg free shipping,603 participants), cardiovascular death was non-signifcantly increased with dual therapy (single 1. One obvious problem is the need to extrapolate evidence in some areas from groups of people who do not have diabetes, for example regarding smoking cessation. However, because event rates are much higher in people with diabetes (particularly with regard to primary prevention) the gains and cost- effectiveness are also potentially much better, so that the risks of extrapolation of evidence are relatively low. This is especially true because the processes of arterial damage in people with type 2 diabetes are similar pathologically to those occurring in the general population, though usually present to a more abnormal degree. Aspirin is warranted for secondary prevention but its beneft in primary prevention is unclear. Implementation the recommendations require access to measurement of a full lipid profle and supporting biochemistry, and to aspirin and statins as a minimum. Number of people with type 2 diabetes seen in Percentage of people Total number of people the past year who smoke Documentation of with type 2 diabetes who with type 2 seen in the as a percentage of the smoking status. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. Comparison of cardiovascular risk between patients with type 2 diabetes and those who had had a myocardial infarction: cross sectional and cohort studies. Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Evidence-based practice guidelines for the assessment of absolute cardiovascular disease risk. New Zealand cardiovascular guidelines handbook: a summary resource for primary care practitioners. Canadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada. Prevention of cardiovascular disease: guidelines for assessment and management of cardiovascular risk. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. The benefts of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. A systematic review and economic evaluation of statins for the prevention of coronary events. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Effects of fbrates on cardiovascular outcomes: a systematic review and meta-analysis. Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus: meta- analysis of randomised controlled trials. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specifc meta-analysis of randomized controlled trials. Aspirin for the primary prevention of cardiovascular events: a systematic review and meta- analysis comparing patients with and without diabetes. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. Aspirin for primary prevention of cardiovascular events in patients with diabetes: a meta-analysis. No advice is given on the further investigation of retinopathy by an ophthalmic specialist, or the subsequent use of laser or other retinal therapy, of vitrectomy, or other tertiary care. It is noted that a substantive evidence-base does exist for these techniques in the prevention of visual loss. Rationale Diabetic retinopathy is the most common complication of diabetes and a major cause of visual loss. Damage (maculopathy) to the area of the retina used for fne and central vision (the macular area around the fovea) is the most signifcant problem in people with type 2 diabetes, though classical retinopathy with new vessels and consequent problems is also important. Interventions to control blood glucose, blood pressure and blood lipids (discussed elsewhere) can help to prevent or delay the onset of retinopathy and slow its progression, but most people with retinopathy will be asymptomatic until the damage is advanced. Early detection by regular surveillance is thus essential if people with sight- threatening retinopathy are to be identifed in time to offer laser treatment to prevent visual loss. New therapies are being developed for retinopathy although current and improved laser photocoagulation and vitrectomy will continue as essential interventions to reduce severe visual loss from focal and diffuse diabetic macular oedema and proliferative diabetic retinopthy. Promising therapies for diabetic retinopathy include intraocular corticosteroids, inhibitors of growth 82 hormone, anti-vascular endothelial growth fact agents and oral protein kinase inhibitors. Inhibitors of androgen receptors, anti-infammatory agents and inhibitors of leukostasis could also prove effective medications to prevent early diabetic retinopathy. Combination therapy aimed at different targets may prove more effective in delaying or preventing diabetic retinopathy [1]. The ?gold standard? screening test of seven- standard feld stereoscopic colour fundus photography and associated grading scheme were established by these studies. In recent years technological developments in digital photography have offered expanding opportunities for recording and transmitting images, with potential for automated grading [6]. The importance of screening people with type 2 diabetes at diagnosis relates to the fnding that between 21 and 39% already have some retinopathy [2,7] and is sight-threatening in about 3% [8]. For people who have no retinopathy at diagnosis of type 2 diabetes, there is a very small chance of developing sight-threatening retinopathy. The Liverpool Diabetic Eye Study reported the 1 year cumulative incidence of sight-threatening diabetic retinopathy in people with type 2 diabetes who at baseline had no diabetic retinopathy, had background retinopathy, or had mild pre-proliferative retinopathy. Guidelines are divided about the frequency of screening in people found not to have retinopathy at the initial examination. Cataract is another important cause of visual loss in people with diabetes, being twice as common as in people without diabetes. The Steno-2 study demonstrated that subjects receiving intensive multifactorial treatment had a signifcantly lower risk of retinopathy (hazard ratio, 0. Quality screening procedures are crucial to ensure timely detection of retinopathy and intervention to prevent or minimise visual loss [13]. Screening options include ophthalmologists, optometrists and other trained medical examiners using dilated ophthalmoscopy or slit lamp biomicroscopy. In the 83 absence of a dilated fundus examination by a trained examiner, non-mydriatic (or mydriatic) photography can be used. The level of sensitivity needed for the screening test cannot be defned unequivocally. Screening examinations or tests should aim for a sensitivity of at least 60%, though higher levels are usually achievable. It is considered that mild diabetic retinopathy missed at one visit would likely be detected at the next. Specifcity levels of 90-95% and technical failure rates of 5-10% are considered appropriate. Cost-effectiveness of screening is dependent on the sensitivity and specifcity of screening tests, attendance and prevalence of diabetic retinopathy. Consideration the core issue is how to provide regular structured review using either ophthalmological expertise or camera technologies. With regard to the latter, use of digital cameras with eyes dilated to reduce the incidence of screen failures is cost-effective. However, camera technologies cannot detect macular oedema, so visual acuity testing must accompany photography. Where neither camera technologies nor ophthalmologists are available, ophthalmoscopy by a trained observer can detect many problems (though with signifcantly poorer sensitivity). The availability of laser therapy is currently limited in many parts of the world due to cost and lack of trained expertise. It is noted that raising awareness of eye problems by examination and recording of detected problems can both help individual preventative care (blood glucose and blood pressure control) and provide the necessary evidence for establishment of a laser service. Implementation Staff requirements are suffcient numbers of experienced ophthalmologists, optometrists and other health-care professionals to perform the screening, and suffcient ophthalmologists to perform laser therapy, and training of such staff. Equipment for screening and treatment will be required, as will a structured recall system and record. All screening modalities require quality assurance checks; for retinal photography it has been suggested this should happen for around 1% of photographs. A national or regional advisory group, including representation of ophthalmologists, optometrists, internists and people with diabetes, can work with health funders to defne such issues as: criteria for screening and treatment; training and education programmes; provision of accessible facilities; awareness programmes; strategies for programme implementation and guideline dissemination; information systems (for monitoring diabetic eye disease, follow-up and recall, collection of baseline and annual data); annual reports based on defned indicators. Evaluation the percentage of records containing the results of eye examination within a 12 month period is easily evaluated. Where such records are of sight-threatening retinopathy or decrease of visual acuity, evidence of review by (or referral to) an ophthalmological specialist should be present. Eye screening services can be checked for appropriately trained personnel and facilities suffcient to ensure 84 diabetes population coverage. Evidence of control of rates of visual loss is more diffcult to gather unless the records of ophthalmological services can be linked to those of diabetes services. Potential indicator Data to be collected Indicator Denominator Calculation of indicator for calculation of indicator Number of people with type 2 diabetes Percentage of people having at least one Documentation and with type 2 diabetes Number of people with eye examination date of the most recent having an eye type 2 diabetes seen in during the past year eye examination. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Accuracy and reliability of teleophthalmology for diagnosing diabetic retinopathy and macular edema: a review of the literature. United Kingdom Prospective Diabetes Study 30: diabetic retinopathy at diagnosis of non-insulin- dependent diabetes mellitus and associated risk factors. Incidence of sight threatening retinopathy in patients with type 2 diabetes in the Liverpool Diabetic Eye Study: a cohort study. Canadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada. Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. No advice is given on further investigation of kidney disease by a renal specialist, or subsequent tertiary care. If test is positive exclude urinary tract infection by microscopy (and culture if possible).

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Some authors suggest that children with a history of vaccine-induced vasculitides 17 should not be revaccinated medications gerd buy oxcarbazepine 150mg line, but there are no clear guidelines for what is the most appropriate management medications given im buy oxcarbazepine 150 mg online. It has been suggested that fu vaccines must be contraindicated in subjects with a history of rheumatoid purpura medications in pregnancy order oxcarbazepine cheap, with previous history of vasculitis after full vaccination symptoms for diabetes purchase 300mg oxcarbazepine, or with active autoimmune rheumatic disease medications held before dialysis purchase oxcarbazepine line. Further investigations are needed to clarify biological plausibility of post-vaccination phenomena. Thus, surveillance systems and registries can be important tools for retrospective as well as prospective evaluations of cases, and also for establishing research studies aimed at elucidating genetic susceptibility factors. Nevertheless, in clinical practice, when the suspicion of vasculitis onset is raised, a meticulous history-taking with special emphasis on vaccine history is imperative, so that an appropriate diagnosis can be established ear- ly and management can be initiated. Moreover, follow-up is mandatory to verify whether a diferent prognosis is associated with these diseases. The lack of evidence for other causes of the symptoms and the coincidence regarding the vaccination in most of the cases analyze here strongly supports a casual relationship between the vaccination and the vasculitis onset, especially where a plausible temporal association exists. For this rea- son, the modal peak in time of the onset has to be carefully examined, in order to detect cases with peak onset within a few days of vaccination (which are more consistent with hypersensitivity reactions) or within weeks or months (which are more consistent with delayed immune reactivity). The term ?undiferentiated? has been used to include all those conditions in which a well-defned diagnosis could not be reached. However, in recent years, signs have demonstrated that, in order to create efective treatments, the underlying etiopathogenic mechanism is more important than the clinical picture. Indeed, when dealing with cancer, the aim of therapy is to destroy the specifc demented cell. When dealing with infections diseases, physicians pay less care if the patient has fever or splenomegaly, as the objective is to kill the pathogenic microorganism. Howev- er, in the feld of autoimmunity, the causes of each disease are multiple, encompassing the ?mosaic of autoim- munity. Physicians should not perhaps be dwelling too much on classifying patients, but instead should aim at discovering the mecha- nisms underlying the pathogenesis of autoimmune disease, as elucidating these mechanisms will be the key to fnding efective preventative therapeutic strategies. Gherardi Francois-Jerome Authier Faculty of Medicine Faculty of Medicine University of Paris East University of Paris East Paris, France Paris, France Josette Cadusseau Faculty of Medicine University of Paris East Paris, France Introduction Over the last century, billions of humans have been vaccinated, and marked regression or eradication of several severe infectious diseases has been observed. Today, the potential applications of vaccines extend far beyond prevention of infectious diseases, and vaccination is considered to be the most promising weapon against a variety of diferent conditions. In general, vaccine safety has been regarded as excellent at the level of the population (Moxon and Sigriest, 2011), but adverse efects have also been reported (Agmon-Levin et al. Given the considerable worldwide development of vaccination, safety signals in the feld require the attention of the medical and scientifc community, even of their intensity seems a priori to be low. Recent demonstrations of their apparent capacity to migrate in lymphoid organs and to progressively accumulate in the brain (Khan et al. Vaccine safety has improved improved in recent years, and the incidence of vaccine-induced autoimmunity is rare, but they are not yet free of risk. It is becoming apparent that is not only the active components that could drive autoantibody production, but also the excipients, such as adjuvant (pristine, aluminum, squalene), or even the residual traces of yeast from the manufacturing process (Rinaldi et al. However, it should be borne in mind that preventative vaccines are usually administered to otherwise healthy subjects who are not yet fght- ing the infectious disease for which they are considered at risk. While the short latency of post-streptococcal-induced rheumatic fever is a few weeks (Arbuckle et al. The temporal relation between vaccinations on immunity depends on the particular vaccine used and its associated phenomena. However, available data are incomplete and difcult to interpret, partly because several factors are thought to be involved in the development of T1D. Well-designed and long-term studies into the use of vaccines and an incidence of childhood diabetes are ongoing. Diferent mechanisms may be involved in this process, including bystander activation of autoreactive B and T cells in response to the vaccine?s adjuvants. Another explanation is molecular mimicry between orexin neuron molecules and the vaccine, the H1N 1 virus, or other infectious agents (e. Finally, all the data together support the relationship between the H1N1 vaccine in the development of narco- lepsy under certain conditions. Therefore, these observations should raise awareness regarding the risks and benefts of H1N1 vaccination versus non-vaccination (Caplan, 2010). Undoubtedly, further insight into the pathogenesis of post-vaccination phenomena and the identifcation of markers of genetic predisposition could be useful in preventing these conditions and in developing personalized and safer vaccines in the future. There are indeed several clinical and paraclinical parameters that clearly diferentiate between the two diseases. Treatments with steroids or anti- body-targeting modalities usually have a favorable efect, and the prognosis is generally good. Autoimmune mechanisms underline many diseases, some organ-specific, others systemic in distribution. Thus the body must establish self-tolerance mechanisms, to distinguish between self and non-self determinants, so as to avoid autoreactivity (see Chapter 7). The self- recognition mechanisms are no exception, and a number of disease have been identified in which there is autoimmunity, due to copious production of autoantibodies and autoreactive T cells. One of the earliest examples in which the production of autoantibodies was associated with disease in a given organ is Hashimoto?s thyroiditis. Among the autoimmune diseases, thyroiditis has been particularly well-studied, and many of the aspects discussed in this chapter will draw upon our knowledge of it. It is a disease of the thyroid which is most common in middle-aged women and often lead to formation of a goiter and hypothyroidism. The gland is infiltrated, sometimes to an extraordinary extent, with inflammatory lymphoid cells. These are predominantly mononuclear phagocytes, lymphocytes and plasma cells, and secondary lymphoid follicles are common (Figure-1). In Hashimoto?s disease, the gland often shows regenerating thyroid follicles but this is not a feature of the thyroid in the related condition, primary myxoedema, in which comparable immunology features are seen and where the gland undergoes almost complete destruction and shrinks. The serum of patients with Hashimoto?s disease usually contains antibodies to thyroglobulin. These antibodies are demonstrable by agglutination and by precipitin reactions when present in high titre. Most patients also have anti bodies directed against a cytoplasmic or microsome antigen, also present on the apical surface of the follicular epithelial cells (Figure-2), and now known to be thyroid peroxidase, the enzyme which iodinates thyroglobulin. The common target organs in organ-specific disease include the thyroid, adrenals, stomach and pancreas. The non-organ-specific diseases, which include the rheumatological disorders, characteristically involve the skin, kidney, joints and muscle (Figure-4) An individual may have more then one autoimmune disease Interestingly, there are remarkable overlaps at each end of the spectrum. Thyroid antibodies occur with a high frequency in pernicious anaemia patients who have gastric autoimmunity, and these patients have a higher incidence of thyroid autoimmune disease than the normal population. Similarly, patients with thyroid autoimmunity have a high incidence of stomach autoantibodies and, to a lesser extent, the clinical disease itself, namely pernicious anaemia. The cluster of hematological disorders at the other end of the spectrum also shows considerable overlap. In these diseases immune complexes are deposited systemically, particularly in the kidney, joints and skin, giving rise to widespread lesions. By contrast, overlap of diseases from the two ends of the spectrum is relatively rare. The mechanisms of immunopathological damage vary depending on where the disease lies in the spectrum. In non-organ-specific autoimmunity, immune complex deposition leads to inflammation through a variety of mechanisms, including complement activation and phagocyte recruitment. This is largely genetic rather than environmental, as many be seen from studies of identical and non-identical twins, and from the associated of thyroid autoantibodies with abnormalities of the X- chromosome. Within the families of patients with organ-specific autoimmunity, not only is there a general predisposition to develop organ-specific antibodies, it is also clear that other genetically controlled factors tend to select the organ that is mainly affected. Thus, although relatives of Hashimoto patients and families of pernicious anaemia patients both have higher than normal incidence and titer of thyroid autoantibodies, the relatives of pernicious anaemia patients have a far higher frequency of gastric autoantibodies, indicating that there are genetic factors which differentially select the stomach as the target within these families. When autoantibodies are fond in association with a particular disease there are three possible inferences:. Autoantibodies secondary to a lesion (the second possibility) are sometimes found. However, sustained production of autoantibodies rarely follows the release of autoantigens by simple trauma. In most diseases associated with autoimmunity, the evidence supports the fist possibility, that the autoimmune process produces the lesions. The pathogenic role of autoimmunity can be demonstrated in experimental models Examples of induced autoimmunity the most direct test of whether autoimmunity is responsible for the lesions of disease is to induced autoimmunity deliberately in an experimental animal and see if this leads to the production of the lesions. Autoimmunity can be induced in experimental animals by injecting autoantigen (self antigen) together with complete Freund?s adjuvant, and this does indeed produce organ-specific disease in certain organs. For example, thyroglobulin injection can induce an inflammatory disease of the thyroid while myelin basic protein can cause encephalomyelitis. In the case of thyroglobulin-injected animals, not only are thyroid autoantibodies produced, but the gland becomes infiltrated with mononuclear cells and the acinar architecture crumbles, closely resembling the histology of Hashimoto?s thyroiditis. The ability to induce experimental autoimmune disease depends on the strain of animal used. Examples of spontaneous autoimmunity It has proved possible to breed strains to animals which are genetically programmed to develop autoimmune diseases closely resembling their human counterparts. So it is of interest that when the immunological status of these animals is altered, quite dramatic effects on the outcome of the disease are seen. For example, removal of the thymus at birth appears to exacerbate the thyroiditis, suggesting that the thymus exerts a controlling effect on the disease, but if the entire T-cell population is abrogated by combining thymectomy with massive injections of anti-chick T-cell serum, both autoantibody production and the attack on thyroid are completely inhibited. Thus, T cells play a variety of pivotal roles as mediators and regulators of this disease. Human autoantibodies can be directly pathogenic When investigating human autoimmunity directly, rather than using animal models, it is of course more difficult to carry out experiments. Nevertheless, there is much evidence to suggest that autoantibodies may be important in pathogenesis, and we will discuss the major examples here. Thyroid autoimmune disease A number of disease have been recognized in which autoantibodies to hormone receptors may actually mimic the function of the normal hormone concerned and produce disease. Graves? disease (thyrotoxicosis) was the first disorder in which such antireceptor antibodies were clearly recognized. Many babies born to thyrotoxic mothers and showing thyroid hyperactivity have been reported, but the problem spontaneously resolves as the antibodies derived from the mother are catabolized in the baby over several weeks. Different combinations of the various manifestations of thyroid autoimmune disease, chronic inflammatory cell destruction and stimulation or inhibition of growth and thyroid hormone synthesis, can give rise to a wide spectrum of clinical thyroid dysfunction (Figure-9). Myasthenia gravis A parallel with neonatal hyperthyroidism has been observed with mothers suffering from myasthenia gravis, where antibodies to acetylcholine receptors cross the placenta into the fetus and may cause transient muscle weakness in the newborn baby. Other receptor diseases Somewhat rarely, autoantibodies to insulin receptors and to? Neuromuscular defects can be elicited in mice injected with serum from patients with the Lambert Eaton syndrome containing antibodies to presynaptic calcium channels, while sodium channel autoantibodies have been identified in the Guillain Barre syndrome. Male infertility Yet another example of autoimmune disease is seen in rate cases of male infertility were antibodies to spermatozoa lead to clumping of spermatozoa, either by their heads or by their tails, in the semen. Pernicious anaemia In this disease an autoantibody interferes with the normal uptake of vitamin B12. Vitamine B12 is not absorbed directly, but must first associated with a protein called intrinsic factor; the vitamin-protein complex is then transported across the intestinal mucosa.