Effect Of MMI Research Articles

Therapeutic effects of methimazole on 3,4-methylenedioxymethamphetamine-induced hyperthermia and serotonergic neurotoxicity

3,4-methylenedioxymethamphetamine (MDMA) is a popular recreational drug, however over 200 studies demonstrate that acute (e.g. hyperthermia, rhabdomyolysis) and chronic (e.g. neurotoxicity) toxicity effects of MDMA were observed in different animals. Methimazole (MMI), an inhibitor of thyroid hormone synthesis, was found to significantly reduce the HSP72 expression of heat stress induced in fibroblasts. Hence, we attempted to understand the effects of MMI on MDMA induced changes in vivo. Male SD rats were randomly divided into four groups as follows:(a) water-saline (b) water-MDMA (c) MMI-saline and (d) MMI-MDMA group. In the temperature analysis test, MMI was found to alleviate MDMA-induced hyperthermia and increase the heat loss index (HLI), revealing its peripheral vasodilation effect. PET experiment suggested that MDMA induced elevated glucose uptake by skeletal muscles, which was resolved by MMI pretreatment. IHC staining (serotonin transporter, SERT) showed the evidence of neurotoxicity caused by MDMA (serotonin fiber loss), which was alleviated by MMI. Furthermore, the animal behaviour test (forced swimming test, FST) showed higher swimming time but lower immobility time in MMI-MDMA and MMI-saline groups. Taken together, treatment of MMI shows benefits such as lowered body temperature, alleviation of neurotoxicity and excited behaviour. However, further investigations should be conducted in the future to provide in-depth evidence for its clinical use.

Adsorption of 2-Mercapto-1-methylimidazole on the (√3 × 22) Reconstructed and (1 × 1) Phases of an Ordered Au(111) Electrode under Potential Control

The self-assembled monolayers (SAMs) of organosulfur compounds bearing an imidazole (Im) functional group can form hydrogen bonds with others and tailor specific interfacial structures used for CO2 reduction, biosensing, and corrosion prevention. The current study employed cyclic voltammetry and in situ scanning tunneling microscopy (STM) to address the adsorption and structure of 2-mercapto-1-methylimidazole (MMI) on the reconstructed and unreconstructed Au(111) electrodes as a function of potential. The adsorbed MMI molecule assumed the unprotonated form, allowing its S- and N-ends to bind with the Au electrode at a positive potential. Molecular resolution STM images showed an ordered Au(111)–(√21 × √21)R10.9°–MMI structure. The Au–N bond could weaken and be broken at a negative potential, leading to a disordered MMI adlayer. This restructuring event was coupled with the protonation of the Im group. These processes resulted in a sharp peak, which shifted negatively by 60 mV with an increase of 1 pH unit. MMI admolecules were desorbed at a more negative potential to unveil a pitted Au surface, resulting from etching of MMI adsorption. This feature supports the S–Au–S motif for MMI adsorbed to the Au(111) electrode, irrespective of the initial Au surface structure. The effect of MMI as an additive to the deposition bath of Ni was also explored.

Temporal hampering of thyroid hormone synthesis just before hatching impeded the filial imprinting in domestic chicks.

Thyroid hormones play a critical role in the initiation of the sensitive period of filial imprinting. The amount of thyroid hormones in the brains of chicks increases intrinsically during the late embryonic stages and peaks immediately before hatching. After hatching, a rapid imprinting-dependent inflow of circulating thyroid hormones into the brain occurs via vascular endothelial cells during imprinting training. In our previous study, inhibition of hormonal inflow impeded imprinting, indicating that the learning-dependent inflow of thyroid hormones after hatching is critical for the acquisition of imprinting. However, it remained unclear whether the intrinsic thyroid hormone level just before hatching affects imprinting. Here, we examined the effect of temporal thyroid hormone decrease on embryonic day 20 on approach behavior during imprinting training and preference for the imprinting object. To this end, methimazole (MMI; a thyroid hormone biosynthesis inhibitor) was administered to the embryos once a day on days 18-20. Serum thyroxine (T4) was measured to evaluate the effect of MMI. In the MMI-administered embryos, the T4 concentration was transiently reduced on embryonic day 20 but recovered to the control level on post-hatch day 0. At the beginning of imprinting training on post-hatch day 1, control chicks approached the imprinting object only when the object was moving. In the late phase of training, control chicks subsequently approached towards the static imprinting object. On the other hand, in the MMI-administered chicks, the approach behavior decreased during the repeated trials in the training, and the behavioral responses to the imprinting object were significantly lower than those of control chicks. This indicates that their persistent responses to the imprinting object were impeded by a temporal thyroid hormone decrease just before hatching. Consequently, the preference scores of MMI-administered chicks were significantly lower than those of control chicks. Furthermore, the preference score on the test was significantly correlated with the behavioral responses to the static imprinting object in the training. These results indicate that the intrinsic thyroid hormone level immediately before hatching is crucial for the learning process of imprinting.

Influence of the metal - support and metal - metal interactions on Pd nucleation and NO adsorption in a Pd4/γ-Al2O3 (110D) model.

The role played by the metal - support (MSI) and metal - metal (MMI) interactions on two important processes in controlling the catalyst performance - nucleation and molecular adsorption - has been investigated using density functional theory (DFT), by means of B3LYP functional, combined with localized molecular orbital energy decomposition analysis (LMOEDA), and natural bond orbital (NBO) calculations, with aid of a Pd4/γ-alumina (110D) model (Pd4/Al13O23H7). Our results indicate the occurrence of an electronic metal - support interaction (EMSI) which induces a most intense charge transfer in the Pd4 → γ-alumina backdonation direction, most expressive in Pd → Al, promoting an electronic redistribution within the units and attenuating the MMI. Nevertheless, the MSI/MMI synergistic effect seems to favor slightly the nucleation of a fifth palladium atom, leading to a distorted square pyramidal arrangement for Pd5. The LMOEDA analysis points to a mostly covalent character in the Pd - Al bonds, whereas the Pd - O bonds are mainly electrostatic in nature. The palladium atoms deposited on oxygen anions are the acid centers, where both NO molecule and an additional palladium atom anchor more strongly. In addition, the MSI/MMI effect, through the electronic and geometric contributions, drives the adsorption of the NO molecule to the mode which most favors the Pd → NO (4dz2 → 2π*) backdonation (bridge mode). MSI and MMI effects on the nature of the Pd - O (electrostatic) and Pd - Al (covalent) bonds, charge transfer into Pd4/γ-Al2O3 (110D) interface (back donation) and preferential site for adsorption of a single NO molecule and an additional Pd atom (Pd - O).

Larval metamorphosis is inhibited by methimazole and propylthiouracil that reveals possible hormonal action in the mussel Mytilus coruscus

Larval metamorphosis in bivalves is a key event for the larva-to-juvenile transformation. Previously we have identified a thyroid hormone receptor (TR) gene that is crucial for larvae to acquire “competence” for the metamorphic transition in the mussel Mytilus courscus (Mc). The mechanisms of thyroid signaling in bivalves are still largely unknown. In the present study, we molecularly characterized the full-length of two iodothyronine deiodinase genes (McDx and McDy). Phylogenetic analysis revealed that deiodinases of molluscs (McDy, CgDx and CgDy) and vertebrates (D2 and D3) shared a node representing an immediate common ancestor, which resembled vertebrates D1 and might suggest that McDy acquired specialized function from vertebrates D1. Anti-thyroid compounds, methimazole (MMI) and propylthiouracil (PTU), were used to investigate their effects on larval metamorphosis and juvenile development in M. coruscus. Both MMI and PTU significantly reduced larval metamorphosis in response to the metamorphosis inducer epinephrine. MMI led to shell growth retardation in a concentration-dependent manner in juveniles of M. coruscus after 4 weeks of exposure, whereas PTU had no effect on juvenile growth. It is hypothesized that exposure to MMI and PTU reduced the ability of pediveliger larvae for the metamorphic transition to respond to the inducer. The effect of MMI and PTU on larval metamorphosis and development is most likely through a hormonal signal in the mussel M. coruscus, with the implications for exploring the origins and evolution of metamorphosis.

The Interface Characterization of 2-Mercapto-1-methylimidazole Corrosion Inhibitor on Brass

This work presents a detailed surface analytical study and surface characterization, with an emphasis on the X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) analyses of 2‑mercapto‑1‑methylimidazole (MMI) as a corrosion inhibitor for brass. First, the electrochemical measurements demonstrated a corrosion inhibition effect of MMI in a 3 wt.% NaCl solution. Next, the formation of the MMI surface layer and its properties after 1 month of immersion was analyzed with attenuated total reflectance–Fourier-transform infrared spectroscopy, atomic force microscopy, field-emission scanning electron microscopy, and contact angle analysis. Moreover, to gradually remove the organic surface layer, a gas cluster ion beam (GCIB) sputtering source at different accelerated voltages and cluster sizes was employed. After each sputtering cycle, a high-resolution XPS analysis was performed. Moreover, an angle‑resolved XPS analysis was carried out for the MMI-treated brass sample to analyze the heterogeneous layered structure (the interface of the MMI organic/inorganic brass substrate). The interface properties were also investigated in detail using ToF-SIMS for spectra measurements and 2D imaging. Special attention was devoted to the possible spectral interferences for MMI‑related species. The thermal stability of different MMI-related species using molecular-specific signals without possible spectral interferences was determined by performing a cooling/heating experiment associated with ToF-SIMS measurements. It was shown that these species desorbed from the brass surface in the temperature range of 310–370 °C.

Side Effects of PTU and MMI in the Treatment of Hyperthyroidism: A Systematic Review and Meta-Analysis

Objective: The present study aimed to investigate the adverse effects of the antithyroid drugs propylthiouracil (PTU) and methimazole (MMI)/carbimazole (CMZ) in treating hyperthyroidism. Methods: Qualitative analysis was performed for studies identified in a literature search up to April 20, 2019, and 30 studies were selected for meta-analysis. The study designs included case-control, randomized controlled, and retrospective cohort. Patients were in four age groups: childhood, gestating mothers, older adults, and other ages, and all were receiving PTU or MMI/CMZ. Adverse reactions to MMI/CMZ and PTU were evaluated and compared. Results: Odds of liver function injury were higher in the PTU group than in the MMI/CMZ group (odds ratio [OR], 2.40; 95% confidence interval [CI], 1.16 to 4.96; P = .02). Odds of elevated transaminase were much higher in the PTU group than in the MMI/CMZ group (OR, 3.96; 95% CI, 2.49 to 6.28; P<.00001). No significant between-group differences were found in odds of elevated bilirubin, agranulocytosis, rash, or urticaria; incidence of other adverse events; or in children. Odds of birth defects during the first trimester of pregnancy were higher in the MMI/CMZ group than in the PTU group (OR, 1.29; 95% CI, 1.09 to 1.53; P = .003). Conclusion: The impact of PTU on liver injury and transaminase levels is greater than that of MMI/CMZ, but no significant between-group differences are found in the drugs' effects on bilirubin, agranulocytosis and rash, urticaria, or in children. In treating pregnancy-related hyperthyroidism, PTU should be used in the first trimester and MMI reserved for use in late pregnancy. Abbreviations: ALT = alanine aminotransferase; ATD = antithyroid drug; CI = confidence interval; CMZ = carbimazole; GD = Graves disease; MMI = methimazole; MTU = methylthiouracil; NOS = Newcastle-Ottawa Scale; OR = odds ratio; PTU = propylthiouracil; RAI = radioactive iodine.

Short Call Abstracts

Short Call Abstracts

Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells

Mono-methylindoles (MMI) were described as agonists and/or antagonists of the human aryl hydrocarbon receptor (AhR). Here, we investigated the effects of MMI on AhR-CYP1A pathway in human hepatocytes and HepaRG cells derived from human progenitor hepatic cells. All MMI, except of 2-methylindole, strongly induced CYP1A1 and CYP1A2 mRNAs in HepaRG cells. Induction of CYP1A genes was absent in AhR-knock-out HepaRG cells. Consistently, CYP1A1 and CYP1A2 mRNAs and proteins were induced by all MMIs (except 2-methylindole), in human hepatocytes. The enzyme activity of CYP1A1 was inhibited by MMIs in human hepatocytes and LS180 colon cancer cells in a concentration-dependent manner (IC50 values from 1.2 μM to 23.8 μM and from 3.4 μM to 11.4 μM, respectively). Inhibition of CYP1A1 activity by MMI in human liver microsomes was much weaker as compared to that in intact cells. Incubation of parental MMI with human hepatocytes either diminished (4-methylindole, 6-methylindole) or enhanced (7-methylindole) their agonist effects on AhR in AZ-AHR reporter cells. In conclusion, overall effects of MMI on AhR-CYP1A pathway in human cells comprise the induction of CYP1A genes through AhR, the inhibition of CYP1A catalytic activity and possibly the metabolic transformation causing loss or gain of AhR agonist activity of parental compounds.

Inhibitory effects of methimazole and propylthiouracil on iodotyrosine deiodinase 1 in thyrocytes.

Methimazole (MMI) and propylthiouracil (PTU) are commonly used for the treatment of Graves' disease. They share similar inhibitory effects on thyroid hormone biosynthesis by interfering with thyroid peroxidase (TPO)-mediated oxidation and organification of iodine. However, their potential effects on other thyroid functional molecules have not been explored in depth. To identify novel effects of MMI and PTU, DNA microarray analysis, real-time PCR, Western blotting, immunofluorescence staining and confocal laser scanning microscopy were performed using FRTL-5 rat thyroid cells. DNA microarray analysis indicated that both MMI and PTU suppress iodotyrosine deiodinase 1 (Iyd, Dehal1) mRNA levels. Further studies revealed that Dehal1 mRNA levels was stimulated by TSH, insulin and serum, while it was suppressed by iodine and a follicular concentration of thyroglobulin. MMI and PTU significantly suppressed Dehal1 expression induced by TSH, insulin and serum. On the other hand, although MMI suppressed Dehal1 expression in the absence of TSH, PTU only weakly suppressed Dehal1 without TSH. These results suggest that PTU and MMI may use different mechanisms to regulate Dehal1 expression, and TSH may play essential and differential roles in mediating PTU and MMI signals in thyrocytes. The drugs also inhibited re-distribution of Dehal1 protein into newly formed lysosomes following thyroglobulin endocytosis. These findings imply complex and multifaceted regulation of Dehal1 in the thyroid and suggest that MMI and PTU modulate Dehal1 expression and distribution of the protein in thyrocytes to exert their effect.

Severe Cholestatic Jaundice: A Rare Adverse Reaction of Methimazole

Methimazole (MMI) is a widely used and generally well-tolerated antithyroid medication. Generally, adverse reactions to antithyroid drugs occur in less than 10% of patients being treated for hyperthyroidism. In this case report, we present a patient who developed hepatotoxicity from MMI treatment. A 51-year-old female with Hashimoto's thyroiditis and Graves' orbitopathy presented to the emergency room with painless jaundice. Her Graves' orbitopathy was refractory to orbital decompression surgery and steroids, thus she was started on MMI six weeks prior to presentation. On admission, her skin exam was significant for jaundice and her abdomen was nontender. Laboratory studies showed alanine aminotransferase (ALT) 1366 IU/L, aspartate aminotransferase (AST) 853 IU/L, total bilirubin 26.2 mg/dL, alkaline phosphatase 954 IU/L, and albumin 3.4 g/dL. Her coagulation profile was normal. Magnetic resonance cholangiopancreatography showed normal biliary tree anatomy without obstruction and computed tomography (CT) of her abdomen showed a normal-appearing liver. Extensive serologic work-up for other causes of liver disease including viral hepatitis, autoimmune hepatitis, primary biliary cholangitis, alpha-1 antitrypsin deficiency, and Wilson's disease were negative. Thus, the patient's liver disease was attributed to drug-induced liver injury from MMI. The drug was held throughout her hospitalization and she was started on ursodiol. ALT peaked at 1,847 IU/L, AST 1,028 IU/L, alkaline phosphatase 1,173 IU/L, and total bilirubin 34.6 mg/dL. Upon discharge one week later, ALT was 340 IU/L, AST 66 IU/L, alkaline phosphatase 466 IU/L, and total bilirubin 7.6 mg/dL. Hepatic synthetic function remained intact and the patient remained asymptomatic.There have been less than 30 case reports of MMI-induced liver injury reported in the literature. Propylthiouracil (PTU) is considered to be more hepatotoxic than methimazole, as PTU is known to cause hepatocellular necrosis. However, while there are case reports of MMI leading to severe hepatitis or liver failure, liver toxicity is not a widely acknowledged side effect of MMI. The mechanism of MMI-induced liver injury is unclear, but it appears to have potential to cause severe cholestasis and hepatitis. Fortunately, the drug-induced liver injury appears to be reversible, as demonstrated by this case in which liver enzymes decreased dramatically with cessation of MMI and administration of ursodiol.

Methylamine irisolidone, a novel compound, increases total ATPase activity and inhibits apoptosis in vivo and in vitro

We propose to further research the protective effect of MMI on myocardium ischemic rat model and H9c2 cells that underwent cell apoptosis induced by hypoxia. We established the myocardium ischemic rat model via the cardiac surgical procedures in vivo and treated the model rats with different concentration of MMI. In vitro, with the pretreatment of MMI for 12 h in the model of Na2S2O4-induced hypoxia injury, the H9c2 cells viability was determined by MTT assay. We found that MMI had significantly improved cardiac function of the myocardial ischemia, and significantly decreased the reactive oxygen species level. The expression of P53, Bcl-2, Bax, and caspase-9 was also induced by MMI. In vitro study revealed a concentration-dependent increase in cell viability associated with MMI pretreatment. Annexin V-FITC and PI staining results showed that MMI had a preventive effect on hypoxia-induced apoptosis in H9c2 cells. MMI also inhibited the mitochondrial membrane potential decrease and increased total ATPase activity during hypoxia in H9c2 cells. In conclusion, MMI can enhance the cardiac function in myocardial ischemic rat and increase cell viability and attenuate the apoptosis in H9c2 cells induced by hypoxia, which was associated with inhibiting MMP decreasion and increasing total ATPase activity.

Successful Re-administration of Low-dose of Methimazole (MMI) in Graves' Disease Patients Who Experienced Allergic Cutaneous Reactions to MMI at Initial Treatment and Had Received Long-term Propylthiouracil (PTU).

Objective When patients with Graves' disease show severe allergic cutaneous reactions, physicians often suggest that they undergo radioiodine therapy instead of receiving propylthiouracil (PTU), another antithyroid drug, because anti-neutrophil cytoplasmic antibody (ANCA) -related vasculitis can occur with PTU, especially with long-term use. However, some patients refuse radioiodine therapy and chose PTU. Sometimes PTU treatment may be prolonged. Since the frequency of adverse effects of methimazole (MMI) is dose-related, there is a possibility that we can re-administer a low dose without adverse effects to patients well-controlled with PTU who once experienced an allergic reaction to MMI. Methods I prospectively re-administered a low dose of MMI to patients who previously experienced an allergic reaction to MMI at initial treatment. The dose of re-administered MMI ranged from 5 mg twice a week to 5 mg daily. Patients Nine patients with Graves' disease who developed urticaria at initial treatment with MMI and had been treated with PTU for 6 to 21 years were recruited. Results Eight of the 9 patients were successfully controlled with MMI without allergic cutaneous reactions. Only one patient felt itchiness 2 days after switching to MMI. However, skin change was not observed. Conclusion If the patients show allergic cutaneous reactions as a side effect of MMI at the initial treatment for Graves' disease, then there is a strong possibility that such patients can tolerate a low dose of MMI without adverse effects after the disease activity has subsided.

Protective effects of GM-CSF in experimental neonatal hypothyroidism

Hypothyroidism induced by methimazole (MMI), has a negative impact on the postnatal development. Neonatal Granulocyte Macrophage-Colony Stimulating Factor [GM-CSF; 50μg/kg, intramuscular injection at postnatal day (PND) 17] had been tested to ameliorate the effects of MMI [0.05%, (weight per volume; w/v), intraperitoneal injection at PND 15]-induced hypothyroidism in Wistar rats. The hypothyroid conditions due to the administration of MMI produced inhibitory effects on neonatal serum thyroxine (T4), 3,5,3′-triiodothyronine (T3), neutrophil count in bone marrow and blood, cerebellar glutathione (GSH) and acetylcholinesterase (AchE), although it induced stimulatory actions on serum thyrotropin (TSH), growth hormone (GH), insulin growth factor-II (IGF-II), tumor necrosis factor alpha (TNF-α), and cerebellar malondialdehyde (MDA) at PND 19. The treatment with GM-CSF could reverse the depressing and stimulating effects of MMI on these markers except for cerebellar AchE where its enhancement was non-significant (P>0.05) at tested PND. Thus, neonatal GM-CSF may be responsible for suppressing autoimmune responses and preventing hypothyroidism.

Pregnancy outcome in women treated with methimazole or propylthiouracil during pregnancy.

Control of thyroid function in hyperthyroid women during pregnancy is based on antithyroid drugs (ATD) [propylthiouracil (PTU) and methimazole (MMI)]. While a teratogenic effect has been suggested for MMI and, more recently, for PTU, a clear demonstration is still lacking. Aim of this study was to assess the safety of ATD during pregnancy. A total of 379 pregnancies were retrospectively recruited in eight Italian Departments of Endocrinology and divided in five groups: (1) MMI-treated and euthyroid throughout pregnancy (n = 89); (2) MMI-treated and hyperthyroid on at least two occasions (n = 35); (3) PTU-treated women and euthyroid throughout pregnancy (n = 32); (4) PTU-treated women and hyperthyroid on at least two occasions (n = 20); and (5) non-ATD-treated (n = 203). Data on maternal thyroid function, miscarriages, type of delivery, neonatal weight, length and TSH, perinatal complications and congenital malformation were analyzed. The gestational age at delivery, the rate of vaginal delivery, neonatal weight, length and neonatal TSH did not significantly differ among groups. In all groups, the rates of spontaneous miscarriage and of major congenital malformations were not higher than in the general population. No newborns were born with a phenotype similar to those described in the "MMI embryopathy". While a clear demonstration of a teratogenic effect of MMI is currently lacking, it seems reasonable to follow the current guidelines and advice for PTU treatment in hyperthyroid women during the first trimester of pregnancy. Further, large and prospective worldwide studies will be needed to fully clarify the issue of ATD safety during pregnancy.

Developmental exposure to methimazole increases anxiety behavior in zebrafish.

The role of thyroid hormones in vertebrate development has been well documented for several decades. As hypothyroidism during critical periods of development can cause defects to the development of every major organ system, including brain, eye, and general morphology, we hypothesized that hypothyroidism would affect specific behaviors. To assess this, we treated zebrafish with the hypothyroid drug methimazole (MMI) and examined changes in anxiety, shoaling, vision, and locomotion. Following low-dose MMI exposure for the first 10 days of life, a time of rapid and significant development, larvae were removed from treatment and allowed to develop until 1 month of age. Comparisons between treated and controls took place between 10 and 30 days postfertilization to examine times both during and after treatment. Using the novel tank and startle response tests, we found that anxiety behaviors are significantly increased following MMI treatment. These effects persisted for several days following removal from treatment and indicate a prolonged effect of early hypothyroidism. However, permanent MMI effects on anxiety were not observed, as anxiety behaviors of early treated zebrafish recovered to control levels following 10 days out of treatment. In contrast to the strong link between MMI treatment and anxiety, shoaling and visual behaviors were not significantly affected within our experimental parameters. This indicates that disruption of thyroid system functioning early in life can differentially affect behavior by specifically altering anxiety responses without producing indiscriminate changes to overall behavioral development.

Therapeutic effectiveness of potassium iodine in drug-naïve patients with Graves’ disease: a single-center experience

Iodine is beneficial against Graves' thyrotoxicosis, though its effects are short-lived. However, its long-term effectiveness as an initial therapy has not been fully elucidated. Here, we compared the effects of potassium iodine (KI) and methimazole (MMI) in Graves' thyrotoxicosis and on thyrotropin receptor antibody (TRAb) levels. Between 2008 and 2011, 293 patients with untreated Graves' disease visited the outpatient clinic of Juntendo University. Of these, 227 patients were treated with MMI and 30 treated with KI as the initial therapy. To compare the effects of KI and MMI, we identified patients with similar probabilities of receiving MMI or KI using propensity score (PS) analysis based on the observed clinical features. PS matching created 20 matched pairs of patients with Graves' disease treated with MMI and KI. The baseline characteristics of post-matched patients treated with MMI were comparable to those treated with KI (FT3; 7.16 ± 2.30, 6.56 ± 1.85 pg/ml, FT4; 2.57 ± 0.79, 2.49 ± 0.70 ng/dl, respectively). The initial dose of MMI was 14.0 ± 8.2 mg/day and that of KI was 53.6 ± 11.7 mg/day. Three patients of the KI group did not respond to the monotherapy, requiring the inclusion of antithyroid drugs. One patient on MMI developed moderate skin eruption, but continued the treatment. Patients who continued the initial treatment showed significant and comparable reductions in FT4, FT3 and TRAb by MMI as well as by KI at the end of 12-month treatment. Although patients were limited to mild untreated Graves' disease thyrotoxicosis, KI offers a possible alternative initial treatment for this condition.

Tunable fiber laser based on the refractive index characteristic of MMI effects

Abstract A tunable erbium-doped all-fiber laser has been demonstrated. This tunable laser is based on a tunable fiber filter using the refractive index characteristics of multimode interference effects. A thinner no-core fiber with a diameter of 104 μm is used to fabricate the tunable fiber filter. The joint point of the thinner no-core fiber with SMF is a taper, which improves its sensitivity for refractive index changes. The filter exhibits a very sensitive response to the change of the environmental refractive index, which is about 1000 nm/RIU in the RI range from 1.418 to 1.427. The tunable fiber laser based on the filter achieved a tunability of 32 nm, with the wavelength tuned from 1532 nm to 1564 nm covering the full C-band. The 3 dB bandwidth of the tunable laser is less than 0.02 nm with the signal-to-noise ratio of about 40 dB.

Increase of Interferon-γ Inducible CXCL9 and CXCL11 Serum Levels in Patients with Active Graves' Disease and Modulation by Methimazole Therapy

Chemokine (C-X-C motif) ligand (CXCL)9 and CXCL11 play an important role in the initial phases of autoimmune thyroiditis (AT); however, their serum levels in patients with Graves' disease (GD) have never been evaluated in relation to thyroid function and treatment. To evaluate CXCL9 and CXCL11 serum levels in GD and to relate these parameters to the clinical phenotype, we measured CXCL9 and CXCL11 serum levels in 91 GD patients; 91 AT, 34 nontoxic multinodular goiters (MNGs), 31 toxic nodular goiters (TNGs), respectively; and 91 healthy controls (age- and sex-matched). Mean CXCL9 and CXCL11 levels were higher in GD in comparison with controls, euthyroid AT, MNG, or TNG (p < 0.05, ANOVA; CXCL9: 274 ± 265, 76 ± 33, 132 ± 78, 87 ± 48, and 112 ± 56 pg/mL; CXCL11: 140 ± 92, 64 ± 20, 108 ± 48, 76 ± 33, 91 ± 41 pg/mL, respectively). Hyperthyroid GD patients had significantly higher CXCL9 or CXCL11 than euthyroid or hypothyroid GD patients. GD patients with untreated hyperthyroidism had higher CXCL9 or CXCL11 than hyperthyroid or euthyroid GD patients under methimazole (MMI) treatment. Comparable CXCL9 and CXCL11 levels were observed in newly diagnosed untreated hyperthyroid GD versus untreated patients with relapse of hyperthyroidism after a previous MMI course. Serum CXCL9 and CXCL11 levels are associated with the active phase of GD both in newly diagnosed and relapsing hyperthyroid patients. The reduction of serum CXCL9 and CXCL11 levels in treated patients with GD may be related to the immunomodulatory effects of MMI.

Potential Teratogenicity of Methimazole: Exposure of Zebrafish Embryos to Methimazole Causes Similar Developmental Anomalies to Human Methimazole Embryopathy

While methimazole (MMI) is widely used in the therapy for hyperthyroidism, several groups have reported that maternal exposure to MMI results in a variety of congenital anomalies, including choanal and esophageal atresia, iridic and retinal coloboma, and delayed neurodevelopment. Thus, adverse effects of maternal exposure to MMI on fetal development have long been suggested; however, direct evidence for the teratogenicity of MMI has not been presented. Therefore, we studied the effects of MMI on early development by using zebrafish as a model organism. The fertilized eggs of zebrafish were collected immediately after spawning and grown in egg culture water containing MMI at various concentrations. External observation of the embryos revealed that exposure to high concentrations of MMI resulted in loss of pigmentation, hypoplastic hindbrain, turbid tissue in the forebrain, swelling of the notochord, and curly trunk. Furthermore, these effects occurred in a dose-dependent manner. Precise observation of the serial cross-sections of MMI-exposed embryos elucidated delayed development and hypoplasia of the whole brain and spinal cord, narrowing of the pharynx and esophagus, severe disruption of the retina, and aberrant structure of the notochord. These neuronal, pharyngeal, esophageal, and retinal anomalous morphologies have a direct analogy to the congenital anomalies observed in children exposed to MMI in utero. Here, we show the teratogenic effects of MMI on the development of zebrafish and provide the first experimental evidence for the connection between exposure to MMI and human MMI embryopathy.