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Although regular fetal monitoring is common practice muscle relaxant drugs z buy ponstel 250mg overnight delivery, no evidence has been identified on the effectiveness of any single or multiple techniques and therefore the clinical judgement of an obstetrician experienced in diabetic pregnancy is essential muscle relaxant phase 2 block ponstel 250 mg. The evidence for the accuracy of ultrasound scanning in predicting macrosomia (birth weight >4 spasms side of head buy 250mg ponstel free shipping,000 g) is mixed spasms spasticity muscle ponstel 250mg sale. The accuracy of fetal weight estimation in women with diabetes is at least comparable to women who are not diabetic,353 but for prediction of macrosomia sensitivities ++ 2 have been found to vary from 36-76%, and positive predictive values from 51-85%. The trials reported either equivalent outcomes or improved outcomes (birthweight, macrosomia, large for gestational age) in women 1+ with gestational diabetes. Two randomised control trials have shown that intervention in women with gestational diabetes with dietary advice, monitoring and management of blood glucose is effective in reducing birth weight and the rate of large for gestational age infants,330, 331 as well as perinatal 330 1+ morbidity. In a single study dietary therapy was associated with a reduction in the rate of large for gestational age infants, even with degrees of mild glucose intolerance short of current diagnostic criteria for gestational diabetes, although other outcomes (birth weight, macrosomia, neonatal hypoglycaemia) were not significantly affected. Clinical suspicion that type 1 or type 2 diabetes is present or 4 developing in pregnancy may be raised by persistent heavy glycosuria in pregnancy (2+ on more than two occasions), random glucose >5. Strategies are likely to be simplified for women believed to be low risk based on risk factors (see Table 4). If, after nutritional advice, preprandial and postprandial glucose levels are normal and there is no evidence of excessive fetal growth, the pregnancy can be managed as for a normal pregnancy. Women who are at risk of pre-term delivery should receive antenatal corticosteroids. Women with diabetes have a higher rate of Caesarean section even after controlling for 2+ confounding factors. There is insufficient evidence on the preferred method of cotside blood glucose measurement 4 in neonates; however, whichever method is used, the glucose value should be confirmed by laboratory measurement. However, methods of glycaemic monitoring and interventions were not standardised in the study, so caution is required before extrapolating these findings to term infants. Glycaemic control at six weeks in women with type 1 diabetes, who exclusively breast fed, has 388 2++ been found to be significantly better than those who bottle fed. B Breast feeding is recommended for infants of mothers with diabetes, but mothers should be supported in the feeding method of their choice. Although most medicines are not licensed for use in lactation, specialist reference sources provide information on suitability of medicines in breast feeding. Women with gestational diabetes should be investigated postnatally to clarify the diagnosis and exclude type 1 or type 2 diabetes. The opportunity should also be taken to provide lifestyle advice to reduce the risk of subsequent type 2 diabetes. Appropriate contraception should be provided and the importance of good glycaemic control emphasised. Pre-pregnancy fi Discuss pregnancy planning with women with diabetes of childbearing age at their annual review. These may include: what to do with insulin or tablets appropriate food to maintain blood glucose levels how often to measure blood glucose and when to check for ketones when to contact the diabetes team and contact numbers. Explain what screening involves and what treatment to expect if retinopathy is found. This excess mortality is evident in all age groups, most pronounced in young people with type 1 diabetes, and exacerbated by socioeconomic deprivation. The life expectancy of both men and women diagnosed as having type 2 diabetes at age 40 is reduced by eight years relative to people without diabetes. In addition to its role in identifying patients at risk of diabetic nephropathy (see section 9), microalbuminuria is an independent marker associated with a doubling in cardiovascular risk. A Hypertension in people with diabetes should be treated aggressively with lifestyle modification and drug therapy. The lowering of blood pressure to 80 mm Hg diastolic is of benefit in people with diabetes. The long term follow up of these patients emphasised the need for maintenance of good blood pressure control. A Beta blockers and alpha blockers should not normally be used in the initial management of blood pressure in patients with diabetes. The reduction of events in patients with type 1 diabetes did not differ from patients with type 2 diabetes but did not reach individual statistical significance. Reduction in cardiovascular events 1+ was seen regardless of baseline cholesterol concentrations. People with diabetes experienced no more side effects from statins compared to people without diabetes. B Lipid-lowering drug therapy with simvastatin 40 mg should be considered for primary prevention in patients with type 1 diabetes aged >40 years. However, the case fatality from myocardial infarction is double that of the non-diabetic population. It demonstrated that long term insulin was of no additional benefit, although there was extensive use of insulin at discharge in all treatment groups making interpretation difficult. For patients with type 2 diabetes mellitus, insulin is not required beyond the first 24 hours unless clinically required for the management of their diabetes. This benefit was consistent across all patient subgroups and was independent of the thrombolytic agent used. The greatest benefit was seen in those patients treated within 12 hours of symptom onset. It should not be withheld 1+ due to concern about retinal haemorrhage in patients with retinopathy, and the indications and contraindications for thrombolysis in patients with diabetes are the same as in non-diabetic patients. Since this trial, routine clinical practice has moved to the more widespread invasive investigation of all medium-to-high risk patients to reduce the incidence of recurrent myocardial infarction. The benefits of clopidogrel therapy are likely to be overestimated in the modern era of interventional practice. There appeared to be a modest benefit in the subgroup of patients with clinically evident atherosclerotic disease that included approximately 30% of patients with a history of myocardial infarction within the previous five years. Although immediate beta blocker therapy should be avoided in patients with acute pulmonary oedema and acute left ventricular failure, subsequent cautious introduction of beta blockade is associated with major benefits. Stroke and transient ischaemic attack were reduced by 31% and 59% respectively (p<0. There is insufficient evidence to recommend fibrates, ezetimibe or nicotinic acid for the primary or secondary prevention of cardiovascular outcomes in patients with type 1 or 2 diabetes treated with statins. Unless covered specifically in the following sections, the principles of management are as for patients without diabetes. No evidence was identified on the effect of metformin on hospitalisation due to stroke or myocardial infarction. Sulphonylureas A meta-analysis addressing whether or not sulphonylureas increase or reduce mortality in patients with heart failure and diabetes found too little data to draw a conclusion. No studies addressing whether or not insulin increases or decreases hospitalisation due to heart failure, myocardial infarction or stroke were identified. Two formulations of metoprolol were used in clinical trials of patients with chronic heart failure. Only long-acting metoprolol succinate has been shown to perform better than placebo in reducing mortality. In the short term they can produce decompensation with worsening of heart failure and hypotension. They should be initiated at low dose and only gradually increased with monitoring up to the target dose. There was a significant 1++ reduction in all-cause and coronary mortality, myocardial infarction, the need for coronary revascularisation and fatal or non-fatal stroke. This significant reduction in cardiovascular events is mainly due to the reduction in the incidence of non-fatal myocardial infarction. Subgroup analysis of the trial showed that benefit from perindopril is mainly in patients with a history of myocardial infarction. There is an increased risk of mortality following both coronary bypass surgery and angioplasty; and there is a substantially increased risk of re-stenosis following angioplasty in diabetic patients, partly ameliorated by the use of coronary stents. Much of this increased risk is due to confounding associations, for example female sex, diffuse coronary disease, impaired left ventricular function and renal impairment, rather than the diabetic state itself. Indications for coronary angiography in patients with diabetes with symptomatic coronary disease are similar to those in non-diabetics, recognising the increased risk associated with revascularisation procedures. Patients should be given information to help them recognise the following risk factors: fi smoking fi dyslipidaemia fi hypertension fi hyperglycaemia fi central obesity and a plan made to help them reduce those which affect them. The additional factor to be considered is to obtain and maintain good glycaemic control. Microalbuminuria is defined by a rise in urinary albumin loss to between 30 and 300 mg day.

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Thus spasms from catheter order 250mg ponstel overnight delivery, all patients should be evaluated (both abnormal bilirubin and albumin) risk groups [61] muscle relaxant effects ponstel 500mg without prescription. This may translate into a higher stan- patterns may be used in clinical practice as reliable markers of dardised mortality ratio within this age category muscle relaxant ibuprofen purchase ponstel 500 mg free shipping, particularly prognosis remains to muscle relaxant flexeril 10 mg discount 250 mg ponstel with mastercard be validated. Care should focus around three ‘pillars’ of practice, a) stratification of risk and treatment; b) staging and surveying disease; and c) active patient management. Very recent data show that inadequate biochemical but validation is required [84,85]. The presence of ductopenia predicts Toronto criteria were established retrospectively from small-to- histological stage progression, along with biochemical response medium-sized single-centre longitudinal cohorts. Furthermore, classical histological staging criteria were defined to predict histological stage progression. Treatment failure must be defined on validated surrogate end- points to account for the slow progression of disease, i. In contrast, of predictive information and relatively high disagreement standard serum liver tests under treatment have been exten- rates when separating patients among low- and high-risk sively validated over the last decade as a simple and robust groups [106]. In therapeutic research, both qualitative and quantitative approaches can be rationally applied. Failed alternate ther- (iii) Serum levels of bilirubin and albumin – both parameters apies will not be summarised here, but prior reviews and guide- normal vs. Differ- it should now be considered the method of choice for stratify- ences in trial inclusion criteria, and some without reference to ing patients at trial inclusion. The strongest non-trial evidence of therapeutic efficacy is enrichment is correlated with improvement in serum liver tests provided by an individual patient meta-analysis, conducted by [4,122–124]. An updated Cochrane meta-analysis tally some patients tolerate liquid preparations better. These data suggest that prolonged applied lower dosages than those now considered optimal. In two of these, a composite ‘treatment failure’ measure ference between the groups approached marginal significance in was used; in the third, the percentage change in total serum a fixed-effect model (odds ratio, 0. However, the results were anal- ysed according to intention-to-treat, so the patients who were 19. The premise behind therapy is in part a refiec- (with a P15% reduction from baseline) and a normal serum tion of the association between serum transaminases and bilirubin level. Over the 2-year study per- demonstrated, anda long-termrandomised trial is currentlyongo- iod, patients receiving combination therapy exhibited a signifi- ing for that purpose. However, despite encouraging results, erbationinpruritus,leadingtotreatmentdiscontinuationin1–10% there was a high rate of fibrosis progression (an increase of of patients [130,131]. It is not yet known meta-analysis [137,138] or retrospective analysis to see if corti- whether these consequences impact long-term cardiovascular costeroids are efficacious and positively impact patients with risk. However, concern remains about Fibric acid derivatives the nature of patient ascertainment, and the deterioration of Fibrates exert potent anti-cholestatic effects through the variable some patients with rising bilirubin values. Whilst there is long-standing interest remains limited to small groups of patients with limited follow- regarding these agents in cholestatic liver disease up. In cases of creatinine elevation, counterbalanced by possible negative impact on renal function hyperproduction from muscle may be occurring, and concern [143]. As such, meta-analysis of existing bezafibrate randomised over nephrotoxicity requires ongoing investigation and caution. According to these criteria, a diagnosis can be made vitamin deficiency should be avoided. Some reports have described added cholestasis in late (iii) Florid bile duct lesion on histology. Such patients should undergo (iii) Moderate or severe interface hepatitis on histology. Recommendations It must be kept in mind that the Paris criteria differ from the 22. Controlled clinical trials have not been – and probably will not be – performed in these 24. In patients with moderate interface hepatitis, patients with severe interface hepatitis, and considera- immunosuppression should be considered. It has been suggested that these patients QoL for patients [29], and can be broad. Currently, there is significant variation be aware of corticosteroid side effects, particularly in patients in patient management between centres and individual clinicians with an underlying cholestatic liver disease. These guidelines will help standardise the approach to symp- immunosuppression should be considered in patients in remis- tom management. The Screening for the presence of symptoms by asking patients time interval should be assessed based on the individual. Screening approaches despite a limited evidence base; tolerability is often an issue, can include Likert (a psychometric scale, commonly involved with side effects including bloating and constipation [186]. Patient education continuously evaluated rather than on an ad hoc basis, and is important here (by clinicians and pharmacists) to avoid it is important to re-evaluate symptoms and response to ther- drug interactions. There is also a risk of symptoms recurring after therapy ated, bile sequestrant, however, despite clinicians describing cessation, and most patients require long-term treatment. There are concerns over potential adverse effects with rifampicin (including hepatotoxicity and haemolysis) so 26. Naltrexone should be started at a low dose to avoid opiate withdrawal-like reactions in the first few days of treatment [201]. Long-term tolerability can be an issue, with Pruritus many patients having ongoing opiate withdrawal-like reactions or reduced threshold to pain [202,203]. Many patients, however, will not experience it and its lestatic itch, typically in patients with pruritus unresponsive to absence should not be considered when diagnosing the disease. Follow-up of patients, and evaluation include dry mouth and patients should be warned about this. However, approach to the management of pruritus has been shown to a small trial failed to show benefit over placebo [205]. Nasobiliary (ii) Use of cold water for baths or showers to provide some drainage appears to provide transient relief from itching but symptom relief of pruritus triggered or exacerbated by requires repeated treatments, is technically complicated and heat/warmth (at night). Their use should be restricted to specialist centres and as (iv) Searching for added allergens, especially in patients with salvage therapy for patients with extreme pruritus unresponsive associated hypereosinophilia or IgE-mediated allergy. These include other Cholestatic pruritus is an area of active research, with several autoimmune conditions such as hypothyroidism or autoimmune experimental agents and approaches under development. Pru- targeting the autotaxin/lysophosphatidic acid pathway (recently ritus at night, autonomic dysfunction, dehydration, restless legs, implicated in cholestatic pruritus) are ongoing or in development and concurrent medications (such as beta-blockers) can all be [189,213]. New therapies are likely to emerge soon but need eval- additive factors to fatigue burden. Indeed, there are pilot data to suggest that structured exercise may be Recommendations beneficial when initiated at levels which can be tolerated by fati- gued patients [224]. Attention should be paid to avoid interaction with other medications as a result of its 31. Most patients have sicca symptoms rather than pri- Fatigue mary Sjogren’s syndrome. Clinicians should specifically enquire Fatigue is frequently reported by patients (over 50%) and when about these symptoms. Artificial tears and saliva are often help- severe (as it is in 20% of patients), it is a significant cause of ful. Pilocarpine or cevimeline (muscarinic receptor agonists) can QoL impairment [215–218,6,29]. Patients with sev- components: central fatigue is frequently associated with cogni- ere xerostomia should be given oral hygiene advice to prevent tive impairment (poor memory and concentration), which can be the development of dental caries. Fatigue is not ilant of the risk of oral candidiasis in patients with severe xeros- related to severity of liver disease, with the exception of very tomia. The approach to fati- gynaecologist (there are no concerns from a hepatology per- gue and its management, therefore, needs to run in parallel with spective). Specific guidelines for the management of sicca symp- the management of the underlying disease process, as is the case toms and Sjogren’s syndrome should be consulted for further for pruritus. Patients with refractory symptoms should be ence ongoing fatigue, and thus, transplant for severe fatigue in referred for specialist management, as evolving new therapies the absence of other indications is not appropriate [221]. Patients should be asked specifically about the is effective in post-menopausal female patients [236].

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A baseline visit was carried out by the rheumatologist spasms mid back buy 500 mg ponstel with mastercard, and then monthly until six month and then every two weeks until birth muscle relaxant esophageal spasm ponstel 250 mg generic. The obstetrician made one visit every two weeks during the frst and second trimesters spasms below breastbone generic 500mg ponstel visa, and then weekly until birth muscle relaxant over the counter generic ponstel 250 mg with amex. The 72 patients with two normal Doppler studies gave birth to healthy babies, 88% of them without obstetric complications (low weight, preeclampsia or prematurity). In contrast, only 27% of the 18 women with abnormal Doppler gave birth at term without complications. The monitoring protocol should include a series of clinical and laboratory parameters, maternal and foetus ultrasounds, and foetal echocardiograms to be carried out during each trimester of the pregnancy. This planned care during pregnancy may reduce the mortality and morbidity of mothers and foeti. From the medical viewpoint, we suggest making one visit during the frst trimester, v every 4-6 weeks until week 26 of gestation, and every two weeks from week 27 until birth. During each visit, we suggest monitoring the weight, blood pressure and the presence of v proteinuria, especially in women with risk of lupus nephritis and/or preeclampsia. During this week, a frst Doppler study of uterine arteries may be carried out in order to estimate the probability of preeclampsia in women at risk (those who test positive to antiphospholipid antibodies, have a history of nephritis, preeclampsia and/or v high blood pressure). If the uterine artery Doppler has not been carried out during week 12 or it was abnormal, we recommend carrying it out this week. Treatment with antimalarial drugs Questions to be answered: • Should anti-malarial drugs be maintained if a pregnancy occursfi However, for years there has been speculation about its potentially harmful effect on the developing foetus. The electroretinography studies carried out on three small cohorts of children exposed before birth to anti-malarial drugs (n=31) showed normal results except in the three infants aged 3-7 months, who were submitted to a study of the back of the eye when they were four years old. This control group was randomly selected from women who contacted this information service during pregnancy and exposed to agents that are known not to be teratogenic, within a similar time frame. With respect to major anomalies evaluated during the monitoring of the pregnancy and during the frst year of life, 7/97 were observed in the exposed group and 15/440 in the non-exposed group, a difference close to statistical signifcance (P=0. Regarding anomalies without genetic, chromosomic entity, or congenital infections, 5/95 appeared in the exposed group compared with 15/440 in the control group(P=0. Prevention of obstetric complications in patients with antiphospholipid antibodies Questions to be answered: • What preventive measures should be taken for obstetric complications in patients with antiphospholipid antibodiesfi They also observed a non-signifcant tendency for preeclampsia to be reduced insofar as they did not observe differences in the rate of prematurity or in the weight at birth. Furthermore, in one of them, the treatment was not assigned randomly, but consecutively. The recommendations in patients with a history of foetal death or severe preeclampsia are not grounded in evidence either, given the limited representation of patients with this profle in the published studies. However, they continue to present a higher rate than the controls of complications such as preeclampsia, placenta detachment and intrauterine growth delay. Recommendations We suggest that patients with obstetric antiphospholipid syndrome and a history of v repeated early miscarriages (fi10 weeks) should be treated with aspirin, with or without associated heparin. We suggest that patients with obstetric antiphospholipid syndrome and a history of foetal v death (>10 weeks) or severe preeclampsia with placental insuffciency should be treated with aspirin and heparin at prophylactic doses. We suggest that asymptomatic carriers of antiphospholipid antibodies should be treated v with aspirin. Prednisone at a dose of fi10 mg/day until the 14th week can be used in refractory cases, v although this measure is not risk-free. Assisted reproduction techniques Questions to be answered: • Are assisted reproduction procedures safe and effcient in systemic lupus erythematosusfi Two historical small-sample studies (n=19 and 21, respectively) analysed the safety and effcacy of assisted reproduction procedures, including ovarian stimulation. There were multiple gestations and prematurity (50%) with secondary complication to this in 38% of the births. The disease activity also increased three times more in patients treated with gonadotropins than in those treated with clomifene. The authors concluded that ovarian stimulation was safer when planned and carried out on patients with controlled disease. Prematurity may reach 50% of the births, and more than one third of them may present complications associated with this prematurity. Contraception methods Questions to be answered: • What contraception methods are safe in women with systemic lupus erythematosusfi Results provided were mainly about the disease activity, incidence of fares and vascular complications. The evidence about the hormone contraceptives and cardiovascular events assessed in this review was more limited due to the variability of the studies in terms of quality and outcome measurements. There were no cases of infection in the genital tract or pelvis, or any important haemorrhagic complication. Four and three people in each group discontinued the treatment due to depression, weight gain and headaches. Vascular events included one venous thrombosis, one myocardial infarction and one thrombosis of the posterior tibial artery. This represented a similar incidence of thromboembolism and arterial thrombosis to that observed in another cohort without hormone treatment. There is a tendency to associate a history of use of hormone contraceptives with thromboembolisms. In women with positive antiphospholipid antibodies, we recommend avoiding B combined hormone contraceptives due to having a greater risk of suffering arterial and venous thrombotic phenomena. Cardiovascular risk level and cardiovascular risk assessment Questions to be answered: • Have people with systemic lupus erythematosus got a greater cardiovascular riskfi In a study whose objective was to determine the incidence and risk factors Cohort S. Despite these inter-ethnic numerical differences, statistical signifcance was not reached in any case. The probability of suffering cardiovascular damage depending on the ethnic group was 6. The systolic blood pressure was also higher in Afro-Americans, after adjusting for age and for place of study. Lipoprotein A and C reactive protein also differed between the two groups, with higher levels in Afro-Americans compared with Caucasians. Compared with Caucasian women, more Afro-American women had plaque on the carotid artery (43. The number of traditional risk factors for vascular events was higher in patients who fnally developed it than in those that did not (7. Moreover, the cardiovascular risk factors, disease activity, accumulated damage and biochemical parameters were assessed. Risk factors for the calcifcation of the aorta valve were found to be C reactive protein (P=0. Calculations using classical study equations underestimate the risk and do not entail signifcant differences in the 2- management of risk factors, as shown in the cohort study published in 2009 by O’Neill et al. Other pathologies 4 considered as equivalent in terms of vascular risk, such as diabetes mellitus, require a six-monthly control of the cardiovascular risk factors, if these are controlled well. If one or more risk factors are badly controlled, the assessment would be every three months. Prevention of cardiovascular events Questions to be answered: • Is there evidence about specifc cholesterol fgure targets, or can we only transfer those recommended for other high cardiovascular risk pathologies such as diabetesfi Currently, the recommendations to prevent the cardiovascular risk in the general popula- tion establish some optimal values of cholesterol in blood, in agreement with the risk factors of the individuals. In a second study on this same cohort, they reported that the most frequent cardiovascular risk profle was the presence of 2 risk factors, and within that profle, the most common one was a sedentary lifestyle plus hypercholesterolemia (defned as a serum concentration of more than 200 mg/ dl). Indication for aspirin Questions to be answered: • In which people with systemic lupus erythematosus is the use of aspirin indicatedfi Of the 232 patients, 166 were randomly assigned to two intervention groups, receiving treatment with low doses of aspirin (n=82) and treatment with low doses of aspirin as well as low doses of warfarin (n=84). The 66 patients who did not accept participating in the randomisation, were assigned to the control group. Indication for high blood pressure drugs Questions to be answered: • Is there evidence that favours the use of certain high blood pressure drugs such as angiotensin blockers, in people with systemic lupus erythematosusfi In agreement with their results, the probability of not suffering renal impairment after 10 years was 88. The changes observed in proteinuria, serum albumin, creatinine clearance and blood pressure before and after treatment were compared.

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In contrast to spasms right abdomen 250 mg ponstel fast delivery the rat autoimmune model spasms below left breast cheap 500 mg ponstel fast delivery, in the mouse model for autoimmunity induced by mercury spasms under right rib cage buy cheap ponstel 250 mg, the autoantibody response is specifically targeted towards nucleolar antigens and is associated with induction of antifibrillarin autoantibodies muscle relaxant tea 250 mg ponstel visa. Second, exposure to low doses of mercury can dramatically worsen the development of autoimmune responses in lupus mouse models. A third difference is the nature of the interaction of heavy metals such as mercury with thiol groups and the role of this affinity in the availability of certain thiol-containing molecules for immature cells. They examined data available that suggest that mercury can behave as an adjuvant and trigger autoimmunity responses. This supports the notion that mercury acts by promoting differentiation of autoreactive T cells towards pathological pathways through a “bystander effect”. The importance of genetic factors in the triggering and development of this Th1- and/or Th2-mediated effect and related immune responses. The role and expression of certain chromosome loci are hypothesized as 134 Chemical/Physical Agents and Autoimmunity possible explanations or contributors to this genetic difference in susceptibility to development of immunological disorders. Despite the adverse effects of gold therapy, it is not known whether environmental or occupational exposure to gold causes renal pathology in humans. However, pro- gressive interstitial lung fibrosis was found in goldsmiths (Kirchner et al. Proteinuria and associated glomerular lesions were observed in rabbits fed with a gold oxide-containing diet (Nagi & Khan, 1984). Genetic susceptibility in the induction of autoimmune reactions and immunological disorders is suggested from the differing outcomes seen with exposure to gold in different rat strains. These genetic- based responses are associated with certain chromosome loci that are implicated in control of T cell polarization to either Th1- or Th2- type immune responses. The renal dysfunction in workers and the general population exposed to high levels of cadmium is characterized as the tubular- type nephritis. Chronic exposure of humans to cadmium has, how- ever, frequently resulted in the tubular and glomerular mixed-type nephritis associated with the development of glomerular damage (Bernard et al. Chronic injec- tions of cadmium chloride were earlier found to cause glomerular amyloidosis in rabbits (Castano, 1971). Early studies in Sprague- Dawley rats showed that chronic oral exposure to cadmium via the drinking-water (100 or 200 mg/l) caused immune complex nephritis (Joshi et al. Similarly, the chronic exposure of Sprague- Dawley rats, but not Brown Norway rats, to cadmium (20 or 100 mg/l in drinking-water) induced production of autoantibodies against two components of glomerular basement membrane — i. In vitro cadmium can enhance the proliferative responses of lymphocytes and antibody production without antigen priming. Thus, autoantibodies could be induced by polyclonal activation of B cells due to cadmium. Although these autoantibodies may be involved in autoimmune renal pathogenesis, no direct evidence is available. In many studies of subchronic or chronic exposure, non-essential heavy metals such as cadmium, lead, and mercury were immunosuppressive in animals and consequently decreased host resistance to infectious agents and tumours. Immunostimulation has also been shown to occur at levels 136 Chemical/Physical Agents and Autoimmunity of exposure lower than those associated with immunosuppression, presumably linking to allergic or autoimmune responses. Multiple sclerosis was suggested to be associated with occupational exposure to zinc (Stein et al. Various autoanti- bodies were also found in human subjects exposed to heavy metals. It is noteworthy that induction of autoantibodies to neural proteins can be caused by heavy metal exposure. For example, antibodies to nervous system structural proteins were induced in workers in a nickel–cadmium battery factory (Evans et al. It is also reported that autoantibodies against nucleoplasmic proteins can be induced in mice treated with hexachloroplatinate (Chen et al. Although contribution of these autoantibodies to autoimmune pathogenesis is proposed, direct relevance of these autoantibodies to autoimmunity induced by individual heavy metals has not been established. This potential contribution of lead to autoimmune disease remains a valid concern. Vinyl chloride has also been shown to produce highly reactive metabolites, chloroethylene oxide and chloroacetaldehyde, that have a high affinity for sulfhydryl groups on proteins (Chiang et al. It has also been suggested that oxidation of intracellular thiols, via binding to sulfhydryl groups, may lead to preferential inactivation of cytotoxic T lymphocytes (Yoshida & Gershwin, 1993). The loss of suppressor cell activity as a result of this inactivation could lead to a breakdown in self-tolerance and be a contributing factor in the autoimmune response (Powell et al. Administration of vinyl chloride increased the number of circulating microchimeric white blood cells and the collagen content in the skin of retired breeder Balb/cJ mice (Christner et al. Dermal inflammation and fibrosis similar to that observed in skin from patients with systemic sclerosis or graft versus host disease were observed in vinyl chloride-treated retired breeders, but not in vinyl chloride-treated virgin females or untreated retired breeders. The association between systemic sclerosis (scleroderma) and solvent exposure (primarily in occupational settings) has been investigated in more than a dozen studies to date (Table 11). These studies have fairly consistently reported a 2- to 3-fold increased risk of disease with various forms of solvent exposure. However, a clear consensus has not developed on specific exposures or classes of 138 Chemical/Physical Agents and Autoimmunity chemicals or on the extent to which similar findings are seen in other autoimmune diseases. Some studies on rheumatoid arthritis, sys- temic small-vessel vasculitis, and multiple sclerosis also demonstrate associations with occupational exposure to solvents, but no associa- tion was seen in a large population-based case–control study of systemic lupus erythematosus (Table 11). Studies in laboratory animals have helped elucidate the mech- anisms through which exposure to particular solvents may influence the development or progression of autoimmune disease. Antibodies to malondialdehyde, a product of the oxidative degradation of 140 Chemical/Physical Agents and Autoimmunity polyunsaturated fatty acids, have been demonstrated in patients with systemic lupus erythematosus and scleroderma (Vaarala et al. Biotransformation of trichloroethylene results in the generation of metabolites such as highly reactive aldehydes and oxides. These reactive intermediates can be strong acylating agents, binding to hydroxyl groups and inducing lipid peroxidation. Other metabolites of trichloroethylene have been shown to directly activate T cell responses following in vivo exposures and alter susceptibility to activation-induced cell death (Blossom et al. It has been postulated that solvent-induced lipid peroxidation leads to the formation of reactive intermediates, which can covalently bind to endogenous proteins, resulting in the generation of neoantigens and stimulating an autoimmune response (Chiang et al. Alternatively, reactive aldehydes may activate T cells through Schiff base formation, a transient interaction between the carbonyl and amine groups in physiological systems (Rhodes et al. Some effects are seen in the lung, such as an increased number, but decreased functional ability. These and other mechanisms contribute to an immunosuppressive effect of smoking and an increased suscep- tibility to infections (Sopori, 2002). The association between tobacco use and the risk of inflammatory bowel disease is quite interesting, in part because of the differences seen with respect to ulcerative colitis and Crohn disease (Table 12). An inverse association has been observed between smoking and the risk of ulcerative colitis. Among former smokers, however, disease risk is higher than among never smokers (odds ratio 1. There is some evidence of a dose–response with the amount smoked (cigarettes per day) for both the inverse association among current smokers and the positive association among former smokers (Calkins, 1989). Smokers also showed reduced severity of ulcerative colitis, as assessed by self-reported symptoms, hospitalizations, or medication use (Loftus, 2004). In Crohn disease, however, most epidemiological studies have shown an increased risk among current and former smokers. Vestergaard (2002) reported results from a meta-analysis of 25 studies pertaining to smoking history and Graves disease (hyper- thyroidism), Graves disease with ophthalmopathy, and various forms of hypothyroidism. Current smoking was strongly associated with risk of developing Graves disease (odds ratio 3. One study showed an increasing risk with increasing number of cigarettes per day in current smokers. Some studies were limited to women; in other studies, the number of men was relatively small (20% of the total sample). Nevertheless, there was some indication in the two studies that allowed sex-specific analyses that the association was stronger in women than in men. Stronger associations for never smokers and current smokers were seen with Graves disease with ophthalmopathy (for never smokers, the odds ratio was 4. The only study that presented sex-specific analyses reported a stronger effect in women than in men. Fewer studies are available regarding smoking and hypothyroidism (defined as Hashimoto thyroiditis, clinical hypothyroidism, subclinical hypothyroidism, or autoimmune thyroiditis), and the overall association with hypo- thyroidism was weaker (odds ratio around 1.

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