Epitope analysis of anti-myeloperoxidase antibodies in propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis

Introduction

Increasing evidence has suggested that linear epitopes of antineutrophil cytoplasmic antibody (ANCA) directed to myeloperoxidase (MPO) might provide clues to the pathogenesis of propylthiouracil (PTU)-induced ANCA-associated vasculitis (AAV). This study mapped epitopes of MPO-ANCA in sera from patients with PTU-induced MPO-ANCA (with or without vasculitis) and primary AAV, aiming to analyze certain epitopes associated with the development of PTU-induced AAV.

Methods

Six recombinant linear fragments, covering the whole amino acid sequence of a single chain of MPO, were produced from Escherichia coli. Sera from 17 patients with PTU-induced AAV, 17 patients with PTU-induced MPO-ANCA but without clinical evidence of vasculitis, and 64 patients with primary AAV were collected at presentation. Of the 17 patients with PTU-induced AAV, 12 also had sera at remission. The epitope specificities were detected by enzyme-linked immunosorbent assay by using the recombinant fragments as solid-phase ligands.

Results

Compared with patients with PTU-induced MPO-ANCA but without clinical vasculitis, sera from PTU-induced AAV patients showed significantly higher reactivity against the H1 fragment of MPO (optical density values: 0.17 (0.10 to 0.35) versus 0.10 (0.04 to 0.21), P = 0.038) and could recognize a significantly higher number of fragments (two (none to four) versus one (none to two), P = 0.026). Compared with sera from primary AAV patients, sera from PTU-induced AAV patients had significantly higher reactivity to the P fragment and the H4 fragment (47.1% versus 14.1% P < 0.001; 41.2% versus 14.1%, P = 0.034, respectively), and could recognize a significantly higher number of fragments (two (none to four) versus one (none to two), P = 0.013]. Among the 12 PTU-induced AAV patients with sequential samples, the number of fragments recognized in remission was significantly less than that in initial onset (two (none to four) versus none (none to 0.75), P < 0.001].

Conclusions

Linear epitopes of MPO molecules might be associated closely with PTU-induced AAV. In particular, the P and H4 fragments may be important epitopes in PTU-induced AAV.     

Complete recovery of growth deficits after reversal of PTU-induced postnatal hypothyroidism in the female rat: a model for catch-up growth

Newborn rats of both sexes were treated from birth with the anti-thyroid goitrogen, n-propylthiouracil (PTU) given in the drinking water of the litter (0.1% w/v). One group received the treatment for 25 days, another for 50 days, and a third group for 120 days. The experimental rats showed growth retardation as well as all other classical signs of developmental arrest or delays induced by postnatal hypothyroidism. In order to assess the ability of the hypothyroid animals to recover spontaneously from the retarded state, at days 25, 50 and 120 postnatal the PTU water was replaced with tap water. In each case, within 5-7 days after PTU withdrawal the animals began to show marked compensatory growth accompanied by many signs of behavioral and physiological recovery. In general, the male rats showed higher compensatory growth rates as compared to the females, enabling them to attain significantly higher body weights. However, when growth recovery was followed for up to 6 months it was found that the male rats were unable to attain complete catch-up growth, regardless of the age at which recovery began, while the females of all age groups were able to achieve this goal. In view of the severity of PTU-induced growth retardation, these results suggest significant plasticity of growth processes in the rat, especially in the female. It is suggested that male and female rats recovering from prolonged PTU-induced growth retardation offer a good model system for the study of biochemical, anatomical and physiological aspects of growth recovery and catch-up growth at both the cellular and organismic levels, particularly in relation to the effects of thyroid, growth hormone, and other growth-promoting factors.     

Inhibitory effect of propylthiouracil-induced hypothyroidism in rat on oxidative drug metabolism

The effect of propylthiouracil (PTU) pretreatment on in vivo and in vitro oxidative drug metabolism was determined in the rat. Whereas pentobarbital sleeping time (PBST) and zoxazolamine paralysis time (ZZPT) were used as indices of in vivo drug metabolizing activity, biotransformation of aminopyrine and aniline by hepatic microsomal preparations were used as indices of in vitro drug metabolizing enzymes activities. PTU pretreatment significantly prolonged both PBST and ZZPT. Whereas PTU did not affect microsomal protein concentration or cytochrome P-450 content, it significantly decreased microsomal cytochrome c reductase and aniline hydroxylase activities. These changes in enzymatic activities were observed in microsomal preparations from either non-fasted or 24-hr fasted rats. Our results suggest that PTU-induced hypothyroidism modifies the metabolism and effectiveness or toxicity of concomitantly administered drugs.     

Phenothiourea sensitizes zebrafish cranial neural crest and extraocular muscle development to changes in retinoic acid and IGF signaling

1-Phenyl 2-thiourea (PTU) is a tyrosinase inhibitor commonly used to block pigmentation and aid visualization of zebrafish development. At the standard concentration of 0.003% (200 μM), PTU inhibits melanogenesis and reportedly has minimal other effects on zebrafish embryogenesis. We found that 0.003% PTU altered retinoic acid and insulin-like growth factor (IGF) regulation of neural crest and mesodermal components of craniofacial development. Reduction of retinoic acid synthesis by the pan-aldehyde dehydrogenase inhibitor diethylbenzaldehyde, only when combined with 0.003% PTU, resulted in extraocular muscle disorganization. PTU also decreased retinoic acid-induced teratogenic effects on pharyngeal arch and jaw cartilage despite morphologically normal appearing PTU-treated controls. Furthermore, 0.003% PTU in combination with inhibition of IGF signaling through either morpholino knockdown or pharmacologic inhibition of tyrosine kinase receptor phosphorylation, disrupted jaw development and extraocular muscle organization. PTU in and of itself inhibited neural crest development at higher concentrations (0.03%) and had the greatest inhibitory effect when added prior to 22 hours post fertilization (hpf). Addition of 0.003% PTU between 4 and 20 hpf decreased thyroxine (T4) in thyroid follicles in the nasopharynx of 96 hpf embryos. Treatment with exogenous triiodothyronine (T3) and T4 improved, but did not completely rescue, PTU-induced neural crest defects. Thus, PTU should be used with caution when studying zebrafish embryogenesis as it alters the threshold of different signaling pathways important during craniofacial development. The effects of PTU on neural crest development are partially caused by thyroid hormone signaling.     

A patient with Graves' disease who developed hypothyroidism associated with thyroid stimulation blocking immunoglobulin during anti-thyroid drug therapy

A girl, 12 years of age, developed Graves' disease compounded with rheumatic fever and idiopathic thrombocytopenic purpura. Thrombocytopenia improved under short-term treatment with steroids and her mitral valvular insufficiency, due to the rheumatic fever, disappeared 4 years later. Initially, she had been treated with propylthiouracil (PTU) for 28 months. She suffered a relapse 9 months after stopping PTU and so she was given further PTU therapy. However, hypothyroidism developed 11 months after the initiation of therapy and continued, though further PTU treatment was discontinued. She now receives 1-thyroxine and maintains a euthyroid state. At the onset of the patient's hyperthyroidism, the TSH-binding inhibitor immunoglobulin (TBII) and the thyroid stimulating antibodies (TSAb) were found to be positive. During the remission period, only the thyroid stimulation blocking immunoglobulin (TSBI) was weakly positive. At relapse, only TBII was mildly positive. When hypothyroidism developed, both TBII and TSBI were positive, and TSAb was negative in all testings of her diluted IgGs. The patient's TBII and thyroid dysfunction were unaffected by high-dose intravenous gammaglobulin therapy or by treatment with prednisolone 0.5 mg/kg/day for 2 weeks. In conclusion, the emergence of TSBI during or after anti-thyroid drug therapy might possibly lead to hypothyroidism in patients with Graves' disease.     

Phenylthiourea specifically reduces zebrafish eye size

Phenylthiourea (PTU) is commonly used for inhibiting melanization of zebrafish embryos. In this study, the standard treatment with 0.2 mM PTU was demonstrated to specifically reduce eye size in larval fish starting at three days post-fertilization. This effect is likely the result of a reduction in retinal and lens size of PTU-treated eyes and is not related to melanization inhibition. This is because the eye size of tyr, a genetic mutant of tyrosinase whose activity is inhibited in PTU treatment, was not reduced. As PTU contains a thiocarbamide group which is presented in many goitrogens, suppressing thyroid hormone production is a possible mechanism by which PTU treatment may reduce eye size. Despite the fact that thyroxine level was found to be reduced in PTU-treated larvae, thyroid hormone supplements did not rescue the eye size reduction. Instead, treating embryos with six goitrogens, including inhibitors of thyroid peroxidase (TPO) and sodium-iodide symporter (NIS), suggested an alternative possibility. Specifically, three TPO inhibitors, including those that do not possess thiocarbamide, specifically reduced eye size; whereas none of the NIS inhibitors could elicit this effect. These observations indicate that TPO inhibition rather than a general suppression of thyroid hormone synthesis is likely the underlying cause of PTU-induced eye size reduction. Furthermore, the tissue-specific effect of PTU treatment might be mediated by an eye-specific TPO expression. Compared with treatment with other tyrosinase inhibitors or bleaching to remove melanization, PTU treatment remains the most effective approach. Thus, one should use caution when interpreting results that are obtained from PTU-treated embryos.     

Neonatal exposure to propylthiouracil induces a shift in lymphoid cell sub-populations in the developing postnatal male rat spleen and thymus

Evidence of the connections between the immune system and the thyroid axis is increasingly strong; however, much of the data are focused on immune effects of altered thyroid status in adults or rodents with congenital defects of the pituitary/thyroid axis. The object of the present study was to determine the effects of PTU-induced hypothyroidism on the developing immune system of the rat by focussing on both the spleen and thymus gland. Male Sprague-Dawley rat pups were exposed to PTU through maternal milk by giving the mothers 0.02% PTU in their drinking water starting on the pups' day of birth until day 24 (d24), shortly before weaning on d28. Animals were sampled on days 14, 22, 30, and 91. The mean body weight was decreased in the PTU-treated animals on days 14, 22, and 30. The mean spleen and thymic weights and cellularity were all decreased in the PTU-treated animals on d22 and d30. PTU exposure increased the proportion of NK cells in the spleen on days 14, 22, and 30. The proportion of T-cells was increased on days 22 and 30 with a particular increase in the CD4+ T-cells, resulting in an increase in the ratio of helper T-cells to suppressor/cytotoxic T-cells at d22. PTU also decreased the proportion of splenic B-cells at days 14, 22, and 30 which could explain the increased proportion of both NK and T-cells during these sampling periods. PTU treatment decreased the lytic ability of NK cells at d22, but no functional differences were observed at days 14, 30, 91, despite the increased proportion of NK cells in PTU-exposed animals at days 14, 22, and 30. PTU exposure also increased the proportion of CD4+CD8- cells in the thymus on d22 and caused an increase in both the CD4+CD8- and CD4-CD8+ populations on d30. These data suggest that the effects of temporary, PTU-induced hypothyroidism on the cell populations in the spleen partially result from transient changes in thymic T-cell development, including a shift towards increased CD4+CD8- cells. The data also suggest that temporary hypothyroidism early in development decreases B-cell development in a transient fashion. Temporary hypothyroidism induced from birth to the latter stages of the weaning period induced transitory effects on the spleen, thymus, and immune cell sub-populations--all of which recovered to normal values when the animals matured.     

Specific ganglioside changes in extraneural tissues of adult rats with hypothyroidism

Adults rats with hypothyroidism were prepared by administration of 6-propyl-2-thiouracil (PTU) or methimazole, and the tissues were examined for their gangliosides through methods including glycolipid-overlay techniques. Normal thyroid tissue contained GM3, GD3, and GD1a as the major gangliosides, with GM1, GD1b, GT1b, and GQ1b in lesser amounts. The goitrous tissue of PTU-induced hypothyroid rats had higher concentrations of GM1 and GD1a with a concomitant decrease of GM3. The amount of GT3 in thyroid tissue was increased in hypothyroid animals. While normal liver tissue had a complex ganglioside pattern with a- and b-series gangliosides, the PTU-induced hypothyroid tissue showed a simpler ganglioside profile that consisted mainly of a-series gangliosides with almost undetectable amounts of b-series gangliosides. The expression of c-series gangliosides was suppressed in the hypothyroid liver tissue. Heart tissue had higher contents of GM3 and GT3 than control. No apparent change was observed in the compositions of major and c-series gangliosides in other extraneural tissues (i.e., kidney, lung, spleen, thymus, pancreas, testis, skeletal muscle, and eye lenses), and neural tissues (i.e., cerebrum and cerebellum) from PTU-induced hypothyroid rats. The ganglioside changes of thyroid, liver, and heart tissues were reproduced in corresponding tissues of methimazole-induced hypothyroid rats. These results suggest that hypothyroid conditions affect the biosynthesis and expression of gangliosides in specific tissue and cell types.     

Experimental hypothyroidism inhibits delta-aminolevulinate dehydratase activity in neonatal rat blood and liver

The aim of this study was to investigate the potential relationship between hypothyroidism and delta-aminolevulinate dehydratase (delta-ALA-D) activity in rat blood and liver. Experimental hypothyroidism was induced in weanling rats by exposing their mothers to propylthiouracil (PTU) diluted in tap water (0.05% w/ v), ad libitum, during the lactational period (PTU group). Control (euthyroid) group included weanling rats whose mothers received just tap water, ad libitum, during the lactational period. Reverted-hypothyroid group (PTU + 3,3',5-triiodo-L-thyronine [T(3)]) included weanling rats whose mothers were exposed to PTU similarly to those in the hypothyroid group, but pups received daily subcutaneous injections of T(3) (20 microg/kg, from Postnatal Days 2-20). After the treatment, serum T(3) levels were drastically decreased (around 70%) in the PTU group, and this phenomenon was almost reverted by exogenous T(3). PTU decreased blood delta-ALA-D activity by 75%, and T(3) treatment prevented such phenomena. Erythrocytes and hemoglobin levels were increased by 10% in PTU-treated animals and higher increments (around 25%) were observed in these parameters when exogenous T(3) was coadministered. Dithiothreitol did not change blood delta-ALA-D activity of PTU-exposed animals when present in the reaction medium, suggesting no involvement of the enzyme's essential thiol groups in PTU-induced delta-ALA-D inhibition. PTU did not affect blood delta-ALA-D activity in vitro. These results are the first to show a correlation between hypothyroidism and decreased delta-ALA-D activity and point to this enzyme as a potential molecule involved with hypothyroidism-related hematological changes.     

Elevated insulin/glucagon ratios and decreased cyclic AMP levels accompany the glycogen and triglyceride storage syndrome in the hypothyroid chick

The role of endogenous glucagon and insulin on the hepatic glycogen and triglyceride storage syndrome in propylthiouracil (PTU)-induced hypothyroidism was investigated in the chick. PTU feeding in the diet resulted in a progressive increase in liver glycogen concentration associated with a concomitant decrease in hepatic glucose-6-phosphatase (G-6-Pase) activity. Plasma glucagon level was significantly decreased and insulin significantly increased after two days of PTU administration. These enzyme and hormone changes were associated with a significant increase in hepatic glucose-6-phosphate (G-6-P) and a decrease in cyclic AMP levels. Although our results do not directly prove, the data does suggest that the hepatic glycogen storage syndrome observed in the PTU-induced hypothyroidism in the chick is mediated through changes in pancreatic glucagon and insulin secretion. The extent of glycogen accumulation was inversely related to G-6-Pase which is a rate limiting glycogenolytic enzyme. A significant increase in the plasma insulin/glucagon ratio, along with a significant decrease in the hepatic cyclic AMP concentration, could most likely also account for the excessive hepatic triglyceride accumulation in the PTU-treated chicks.     

Therapeutic exploration of betulinic acid in chemically induced hypothyroidism

Hypothyroidism is a chronic condition characterized by abnormally low thyroid hormone production. The decreased serum level (>5.1 mIU/l) of thyroid-stimulating hormone (TSH) in blood indicates hypothyroidism. The study was an attempt to access the effect of betulinic acid on chemically induced hypothyroidism in female albino rats. Betulinic acid is a naturally occurring pentacyclic triterpenoid, which has antiretroviral, antimalarial, and anti-inflammatory properties, as well as anticancer potential, by inhibiting topoisomerase. Hypothyroidism was induced in female albino rats using propylthiouracil (PTU) at a dose of 60 μg/kg body weight orally for 1 month. Induction of hypothyroidism was confirmed by increased TSH level. At the end of second month, blood was collected, centrifuged and serum was analyzed for TSH, T3, and T4 level and protocol was terminated by killing of animals. The animals exposed to PTU were treated with pure standard drug thyroxine at a dose of 10 μg/kg of body weight by oral route and the test drug betulinic acid 20 mg/kg by oral route through force feeding in their respective groups. Treatment was carried out for a period of 2 months. Group with PTU-induced hypothyroidism showed an elevation in serum TSH and reduction level, which was restored by the betulinic acid in treated female albino rats. Betulinic acid also reduced the damage caused in the thyroid tissues by PTU, thus minimizing the symptoms of hypothyroidism. Histopathological examinations of the thyroid tissue showed changes in the thyrocytes of PTU-treated group while thyroxine group showed normal thyroid follicles cell architecture and the group treated with betulinic acid also showed marked improvement in the follicles integrity which shows that betulinic acid has some protective activity. This study shows that the betulinic acid has thyroid-enhancing potential by lowering down the TSH levels and reducing the damage caused in the thyroid tissues, thus minimizing the symptoms of hypothyroidism when used anaphylactically in rats.     

Effects of thyroid hormones on the evolution of monoamine oxidase activity in the brain and heart of the developing rat

The evolution of monoamine oxidase (MAO) activity towards tryptamine has been studied from birth to 20 days post-natal in the brain and heart of male rats. Hyperthyroidism was induced by thyroxine injections and hypothyroidism by PTU administration. The results are expressed per unit of fresh weight and per unit of protein weight. Cardiac MAO is higher in the hyperthyroid animals than in controls as soon as 5 days following birth; the difference between the 2 groups increases until 20 days. The deficiency in thyroid hormones, on the other hand, was followed by a slight decrease in the cardiac enzyme, this decrease reflecting the general deficit in protein synthesis. Brain MAO is not affected by hyperthyroidism, but a clear deficit follows PTU administration. This deficit is significant beginning at 10 days and the difference between the 2 groups increases up to 20 days. The effects of PTU-induced hypothyroidism can be corrected by thyroxine injections. Except for the decrease in the level of cardiac enzyme in hypothyroid animals, all the effects on MAO activity are independent of the total protein content of both organs.     

Antineutrophil Cytoplasmic Antibody-Positive Vasculitis in A Patient with Graves Disease: Cross-Reaction Between Propylthiouracil and Methimazole

ObjectiveTo alert clinicians about the risk of vasculi- tis and cross-reactivity of antithyroid medication.MethodsWe describe the clinical course and medical management of the study patient.ResultsA 25-year-old woman with hyperthyroid- ism developed antineutrophil cytoplasmic antibody-posi- tive vasculitis after 15 months of propylthiouracil therapy. Her condition improved when propylthiouracil was with- drawn, but recurred when she was prescribed methimazole. Propylthiouracil and methimazole are commonly used an- tithyroid medications, and propylthiouracil is a well-rec- ognized cause of drug-induced vasculitis. Cross-reactivity between the 2 drugs is likely, but it has not been reported previously with regard to vasculitis. Many patients with propylthiouracil-induced vasculitis have been switched to methimazole.ConclusionsAwareness of this rare, but potentially serious, adverse drug reaction is important because prompt discontinuation of medication is essential. Cross-reactivity between propylthiouracil and methimazole must be consid- ered when selecting alternative therapies. (Endocr Pract. 2010;16:449-451)     

Changes in cyclic AMP level of rat thyroid by acute and chronic stimulation of thyrotropin in vivo.

To assess a possible postmortem change in the level of cyclic AMP, the thyroids were snap-frozen at various time intervals after removal. Rats were fed a low-iodine diet (LID) with PTU for 2 weeks and a week after PTU discontinuation (PTU withdrawal). In all cases, the cyclic AMP level tended to increase as time elapsed from removing till fixing the thyroids, but in the PTU withdrawal group, the level was rapidly increased 2-fold after 5 min. In an acute experiment, the thyroids were removed under anesthesia and frozen rapidly. Intravenous administration of ovine thyrotropin (250 mU) and TRH (500 ng) brought about a rapid increase in the thyroidal level of cyclic AMP to 40% to 20% over the control level. Two weeks after PTU treatment, circulating thyrotropin was increased to a maximum of 19-fold and a further enhancement ("rebound") was observed after PTU withdrawal. PTU treatment led to an increase in the thyroidal level of cyclis AMP pre mug DNA to 60% over the control value. Following PTU withdrawal, the rise in the level of cyclic AMP returned to the normal level. However, there was no change in the concentration when it was expressed as per mg wet tissue weight. Therefore, the increase in the thyroidal concentration of cyclic AMP per mug of DNA may be due to an increase in volume of the follicular cells.     

Retinal vasculitis: a diagnostic dilemma

Inflammation of the retinal vasculature, retinal vasculitis, is a poorly understood category of ocular pathology. Patients may or may not be symptomatic. Retinal vasculitis, classified as arteritis or phlebitis, can present as a sole clinical feature or can be accompanied by an anterior uveitis, vitritis, retinal hemorrhages and/or retinal ischemia, thereby making diagnosis difficult. There is evidence that most causes of vasculitis involve an autoimmune response to specific antigens. This disorder may occur in association with infectious disease, systemic inflammatory disorders, primary ocular conditions or as an idiopathic syndrome. Differential diagnosis includes eliminating these etiologies as well as non-inflammatory disorders which can mimic true retinal vasculitis. Proper identification along with timely treatment is crucial in the management of this potentially visually devastating entity. This article provides a current, general guide to the etiology and differential diagnosis of retinal vasculitis. The clinical presentation will be illustrated through four case presentations. The practitioner will also be provided with a tailored approach to management.     

Modulation of gamma-glutamyltranspeptidase activity in rat liver plasma membranes by thyroid hormone

1. In adult male and female rats, liver plasma membrane gamma-glutamyltranspeptidase activities were 16-fold higher in the propylthiouracil (PTU)-induced hypothyroid state than in the control euthyroid state; thyroxine (T4)-replacement resulted in an 80% restoration to control levels. 2. Liver plasma membrane gamma-glutamyltranspeptidase activities were 6.7-fold higher in PTU-induced congenitally hypothyroid rats than in control euthyroid rats; T4-replacement reduced enzyme activities to 37% of control levels. 3. In adult rats, in response to the development and recovery from tri-iodothyronine (T3) excess, liver plasma membrane gamma-glutamyltranspeptidase activities were inversely related to, and out of phase by 12 hr, to the earlier changes in T3. 4. Liver gamma-glutamyltranspeptidase is a thyroid hormone-dependent enzyme.     

Direct effects of propylthiouracil on testosterone production in monkeys

Propylthiouracil (PTU) is an anti-thyroid drug. However, the direct effects of PTU on the endocrine functions of non-thyroid glands are unclear. In the present study, we examined the acute effects of PTU on testosterone secretion in monkeys. Male monkeys were infused intravenously with PTU for 30 min. Blood samples were collected at several time intervals. Monkey testicular interstitial cells were cultured with PTU, human chorionic gonadotropin (hCG), or forskolin, at 34 degrees C for 1 h. In another study, steroidogenesis in monkey testicular interstitial cells were examined. PTU decreased plasma testosterone but not plasma thyroxine (T4) and luteinizing hormone (LH) levels in monkeys. Administration of PTU resulted in a dose-dependent inhibition of basal and hCG-, as well as forskolin-stimulated testosterone release by monkey testicular interstitial cells. PTU also diminished the stimulatory effects induced by androstenedione. These results suggest that PTU inhibits testosterone secretion via a mechanism independent of the secretion of T4 and LH in primates. The inhibitory mechanism of PTU on testosterone production involves a decreased activity of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) and post-cAMP pathways.     

Dobutamine stress magnetic resonance imaging suffices for the demonstration of myocardial ischaemia and viability

We report three patients in whom dobutamine stress magnetic imaging (DS-MRI) was essential in assessing myocardial ischaemia. Two patients were referred to the cardiologist because of chest pain. Patient A had typical exertional angina and a normal resting electrocardiogram (ECG). Patient B had typical exercise-induced angina and had recently experienced an attack of severe chest pain at rest for 15 minutes. The ECG showed a complete left bundle branch block (LBBB). Patient C was referred for heart failure of unknown origin. There were no symptoms of chest pain during rest or exercise. Echocardiography in this patient demonstrated global left ventricular (LV) dilatation, systolic dysfunction and a small dyskinetic segment in the inferior wall. In all these patients exercise stress testing had failed to demonstrate myocardial ischaemia. Patients A and C produced normal findings whereas in patient B the abnormal repolarisation due to pre-existent LBBB precluded a diagnosis of ischaemia.Breath-hold DS-MRI was performed to study LV wall motion and wall thickening at rest through increasing doses of dobutamine. A test was considered positive for myocardial ischaemia if wall motion abnormalities developed at high-dose levels of the drug (20 μg/kg/min or more with a maximum of 40 μg/kg/min) in previously normal vascular territories or worsened in a segment that was normal at baseline. Recovery of wall thickening in a previously hypokinetic or akinetic segment at a low dose of dobutamine (5-10 μg/kg/min) was taken as proof of viability.Patients A and B developed hypokinesia progressing into akinesia at high-dose dobutamine in the anteroseptal area of the LV indicative of ischaemia. These findings were corroborated by coronary angiography demonstrating severe coronary artery disease which led to coronary artery bypass grafting (CABG) in patient A and balloon angioplasty in patient B. In patient C global recovery of LV contractions during low-dose dobutamine was followed by hypokinesia in the inferoseptal area during high-dose dobutamine. This biphasic response indicates myocardial viability as well as ischaemia. CABG was carried out because of multiple stenoses in the left coronary artery. Post-operatively LV function normalised.DS-MRI is a valuable method for detecting myocardial ischaemia and viability in patients with suspected coronary artery, and can be applied in every hospital with MRI equipment at its disposal.     

Churg-Strauss syndrome: a diagnosis not to be forgotten

Churg-Strauss syndrome (CSS) is a peculiar form of vasculitis with involvement of small- and medium-size arteries, histologically characterized by necrotizing granulomas in vessel walls and in perivascular tissues. The Authors report a case of CSS occurred in a young man being treated with corticosteroids for a diagnosis of asthma. The patient was hospitalized because of fever, diarrhoea and abdominal pain; the first assessment showed leucocytosis and eosinophilia,increase in flogosis indexes and anti-pANCA antibodies positive. A few days later an acute peritonitis with multiple intestinal perforations occurred and a partial resection of small bowel was performed,followed by another resection of an ileal segment because of a new double perforation close to the previous intestinal anastomosis. In the bowel resection pieces necrotizing vasculitis and granulomatous infiltrates involving lymphocytes and eosino- phils were observed. Although the severe intestinal involvement and especially the symptoms necessitating iterative surgery were significant factors of poor prognosis the patient was successfully treated firstly with metylprednisolone only and then with monthly administration of immunosuppressive drugs combined with lower daily dose of steroids. The CSS diagnosis is not to be forgotten althoughits early clinical features can be frequently mistaken for an allergic disease; an early diagnosis can allow to perform the best treatment, to reach the disease remission and to improve the quality of life of the patients.     

Central stimulatory effect of leptin on T3 production is mediated by brown adipose tissue type II deiodinase

To assess whether intracerebroventricular leptin administration affects monodeiodinase type II (D2) activity in the tissues where it is expressed [cerebral cortex, hypothalamus, pituitary, and brown adipose tissue (BAT)], hepatic monodeiodinase type I (D1) activity was inhibited with propylthiouracil (PTU), and small doses of thyroxine (T4; 0.6 nmol. 100 g body wt(-1). day(-1)) were supplemented to compensate for the PTU-induced hypothyroidism. Two groups of rats were infused with leptin for 6 days, one of them being additionally treated with reverse triiodothyronine (rT3), an inhibitor of D2. Control rats were infused with vehicle and pair-fed the amount of food consumed by leptin-infused animals. Central leptin administration produced marked increases in D2 mRNA expression and activity in BAT, changes that were likely responsible for increased plasma T3 and decreased plasma T4 levels. Indeed, plasma T3 and T4 concentrations were unaltered by central leptin administration in the presence of rT3. The additional observation of a leptin-induced increased mRNA expression of BAT uncoupling protein-1 suggested that the effect on BAT D2 may be mediated by the sympathetic nervous system.