Drug discontinuation after treatment with minimum maintenance dose of an antithyroid drug in Graves' disease: a retrospective study on effects of treatment duration with minimum maintenance dose on lasting remission.

According to the guideline issued by the Japan Thyroid Association in 2006 for treatment of Graves' disease, discontinuing antithyroid drug (ATD) therapy is recommended when serum free thyroxine (FT4) and thyroid stimulating hormone (TSH) concentrations have been maintained within the reference range for a certain period after treatment with one ATD tablet every other day (minimum maintenance dose therapy, MMDT). In this retrospective study, the relationship between MMDT duration and remission rate was investigated. The participants were 107 consecutive patients with Graves' disease whose ATD therapy was stopped according to the guideline. Serum FT4, TSH, and TSH receptor antibody (TRAb) levels were measured when ATD was discontinued and every 3 months thereafter. The percentage of patients in remission was 86.9% at 6 months, 73.8% at 1 year, and 68.2% at 2 years after ATD discontinuation. The remission rate increased with MMDT duration, being significantly higher in patients with MMDT durations of 19 months or more than those with MMDT durations of 6 months or less. In patients with MMDT durations of 6 months or less, the remission rate was significantly lower in TRAb-positive patients than in TRAb-negative patients at the time of withdrawal of ATD; however, this was not observed in patients with MMDT durations of 7 months or more. These findings suggest that in patients who discontinue ATD after a certain MMDT duration, the remission rate increases as the MMDT duration increases, and ATD should not be discontinued in TRAb-positive patients with MMDT durations of 6 months or less.

Persistent high TRAb values during pregnancy predict increased risk of neonatal hyperthyroidism following radioiodine therapy for refractory hyperthyroidism.

Serum levels of TSH receptor antibody (TRAb) often increase after radioiodine treatment for Graves' disease, and high-serum levels of maternal TRAb in late pregnancy indicate a risk of neonatal hyperthyroidism. The aim of this retrospective study is to investigate the characteristics of Graves' women who had a history of radioiodine treatment for intractable Graves' disease, and whose neonates suffered from hyperthyroidism. The subjects of this study were 45 patients with Graves' disease who became pregnant during the period from 1988 to 1998 after receiving radioiodine treatment at Ito Hospital. 25 of the 45 subjects had had a relapse of hyperthyroidism after surgical treatment for Graves' disease. 19 pregnancies were excluded because of artificial or spontaneous abortion. In the remaining 44 pregnancies of 35 patients, neonatal hyperthyroidism developed in 5 (11.3%) pregnancies of 4 patients. Serum levels of TRAb at delivery were higher in patients whose neonates suffered from hyperthyroidism (NH mother) than those of patients who delivered normal infants (N mother). Furthermore, serum levels of TRAb in NH mother did not change during pregnancy, although those of 4 patients of N mother, in which serum levels of TRAb before radioiodine treatment were as high as in NH mother, decreased significantly during pregnancy. In conclusion, women who delivered neonates with hyperthyroidism following radioiodine treatment seem to have very severe and intractable Graves' disease. Persistent high TRAb values during pregnancy observed in those patients may be a cause of neonatal hyperthyroidism.

Measuring thyroglobulin autoantibodies by sensitive assay is important for assessing the presence of thyroid autoimmunity in areas with high iodine intake.

There is some debate over the clinical utility of measuring serum TgAb to assess the presence of thyroid autoimmunity. To clarify the relationship between TgAb levels and thyroid autoimmunity, a histological examination of thyroid tissue was carried out on unselected living individuals with detectable serum TgAb. 146 patients with a pathological diagnosis of follicular adenoma were selected as subjects. Focal lymphocytic infiltration (FLI) was defined as lymphocytic aggregates of more than 200 in number. A thyroid gland in which 0-1 FLI was observed in a few visual fields of low magnification (20 x 4) in thyroid tissue adjacent to a tumor was judged to be normal and a thyroid gland in which 2 or more FLI were observed was diagnosed as focal lymphocytic thyroiditis (FLT). Serum levels of TgAb and TPOAb were measured by radioimmunoassay. Out of the 146 patients, 18 had detectable serum TgAb and 16 had detectable serum TPOAb. All but one (i.e. 94%) of the 18 TgAb positive patients had FLT and 14 out of the 16 TPOAb positive patients had FLT. The sensitivity (17/32; 53.1%) and specificity (113/114; 99.1%) of TgAb for detecting FLT were higher than those (14/32; 43.7% and 112/114; 98.2%) of TPOAb, but the differences were not significant. In 9 patients who were TgAb positive (but TPOAb negative), 8 (88.9%) had FLT. These results throw doubt on the Laboratory medicine practice guidelines published in Thyroid 2003, in which measuring TgAb is not usually necessary for detecting autoimmune thyroid disease. At least measuring TgAb by sensitive assay is useful for assessing the presence of thyroid autoimmunity in Japan, an area with high iodine intakes.

A novel goose-type lysozyme gene with chitinolytic activity from the moderately thermophilic bacterium Ralstonia sp. A-471: cloning, sequencing, and expression.

In this study, we cloned the gene encoding goose-type (G-type) lysozyme with chitinase (Ra-ChiC) activity from Ralstonia sp. A-471 genomic DNA library. This is the first report of another type of chitinase after the previously reported chitinases ChiA (Ra-ChiA) and ChiB (Ra-ChiB) in the chitinase system of the moderately thermophilic bacterium, Ralstonia sp. A-471 and also the first such data in Ralstonia sp. G-type lysozyme gene. It consisted of 753 bp nucleotides, which encodes 251 amino acids including a putative signal peptide. This ORF was modular enzyme composed of a signal sequence, chitin-binding domain, linker, and catalytic domain. The catalytic domain of Ra-ChiC showed homologies to those of G-type lysozyme (glycoside hydrolases (GH) family 23, 16.8%) and lysozyme-like enzyme from Clostridium beijerincki (76.1%). Ra-ChiC had activities against ethylene glycol chitin, carboxyl methyl chitin, and soluble chitin but not against the cell wall of Micrococcus lysodeikticus. The enzyme produced alpha-anomer by hydrolyzing beta-1,4-glycosidic linkage of the substrate, indicating that the enzyme catalyzes the hydrolysis through an inverting mechanism. When N-acetylglucosamine hexasaccharide [(GlcNAc)6] was hydrolyzed by the enzyme, the second and third glycosidic linkage from the non-reducing end were split producing (GlcNAc)2 + (GlcNAc)4 and (GlcNAc)3 + (GlcNAc)3 of almost the same concentration in the early stage of the reaction. The G-type lysozyme hydrolyzed (GlcNAc)6 in an endo-splitting manner, which produced (GlcNAc)3 + (GlcNAc)3 predominating over that to (GlcNAc)2 + (GlcNAc)4. Thus, Ra-ChiC was found to be a novel enzyme in its structural and functional properties.

Effects of pravastatin on serum osteoprotegerin levels in patients with hypercholesterolemia and type 2 diabetes.

Osteoprotegerin is a secretory glycoprotein. Recent experimental findings have suggested that osteoprotegerin may protect against vascular calcification and/or atherosclerosis. In humans, osteoprotegerin levels are positively correlated with the presence and severity of coronary artery disease and the progression of atherosclerosis. However, it is unclear how osteoprotegerin levels are regulated. Statins are known to have beneficial pleiotropic effects against atherosclerosis beyond their lipid-lowering effects. In this study, we examined whether treatment with pravastatin can alter osteoprotegerin levels in patients with hypercholesterolemia and type 2 diabetes. Osteoprotegerin levels were significantly increased from 6.64 +/- 2.18 pmol/L at baseline to 7.08 +/- 2.29 pmol/L (P = .024) after 3-month treatment with pravastatin. These increases in osteoprotegerin levels remained after 6 months of treatment (7.05 +/- 2.22 pmol/L, P = .026). These findings suggest that pravastatin may exert its pleiotropic effects in part through alteration of osteoprotegerin levels.

Glimepiride increases high-density lipoprotein cholesterol via increasing adiponectin levels in type 2 diabetes mellitus.

The aims of the present study are to investigate the effect of glimepiride 1 mg/d on plasma adiponectin and to assess the contribution of adiponectin in changing high-density lipoprotein cholesterol (HDL-c) levels after glimepiride treatment. Forty patients with type 2 diabetes mellitus were included. Plasma adiponectin, fasting plasma glucose, insulin, hemoglobin A(1c), and cholesterol were measured at study entry and after 3 months of treatment with glimepiride. Both plasma adiponectin level (7.5 +/- 4.5 vs 8.3 +/- 4.5 microg/mL, P = .040) and HDL-c level increased significantly (50 +/- 11 vs 53 +/- 10 mg/dL, P = .041) in the all-subjects group. In the low-adiponectin group (initial plasma adiponectin level <6 microg/mL), both plasma adiponectin level (4.5 +/- 0.9 vs 5.9 +/- 2.0 microg/mL, P = .004) and HDL-c level increased significantly (44 +/- 8 vs 49 +/- 9 mg/dL, P = .011). There was no significant change in the high-adiponectin group (initial plasma adiponectin level >or=6 microg/mL). Change in plasma adiponectin level was an independent factor for change in HDL-c level after adjustment for other factors (beta = .574, P = .009, R(2) = 0.524, P = .036). In conclusion, glimepiride improved plasma adiponectin level, especially in the subjects with type 2 diabetes mellitus with low adiponectin level before treatment, and may directly contribute to improving HDL-c level.