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The dose of L-T4 replacement for hypothyroidism often needs to be increased after pregnancy. In our institution, patients are instructed to double the dose 2 days a week after pregnancy. However, there is scarce evidence supporting the need for a dose increase after pregnancy in patients with preconception thyroid-stimulating hormone (TSH) suppression (TSH

Objective Resistance to thyroid hormone beta (RTHβ) is an inherited syndrome caused by mutations in the thyroid hormone receptor β (THRB) gene. Patients with RTHβ typically have elevated thyroid hormone levels with non-suppressed serum thyroid-stimulating hormone (TSH). We aimed to elucidate the clinical, laboratory, and imaging findings of RTHβ patients and further to explore their association with THRB gene mutations. Design and methods We retrospectively reviewed the clinical charts and compared the clinical findings of 68 RTHβ patients (45 probands and 23 relatives) and 30 unaffected relatives in Kuma Hospital. Results Genetic testing revealed 35 heterozygous THRB gene mutations. Among all RTHβ patients, autoimmune thyroid disease (AITD) was detected in 42.1% of men and 40.9% of women, showing that the prevalence of AITD in affected males was significantly higher than in unaffected relatives (P = 0.019). During the follow-up of 44 patients, 13 patients (29.5%; 8 (42.1%) with AITD and 5 (20%) without AITD) temporarily showed thyroid function test results inconsistent with RTHβ. Two patients with the R383H mutation, which has little dominant-negative effect, temporarily showed normal thyroid hormone and TSH levels without AITD. Conclusions The frequency of AITD in male RTHβ patients was significantly higher compared to unaffected relatives. More than 20% of RTHβ patients temporarily showed laboratory findings atypical of RTHβ during their follow-up, and patients with AITD and specific THRB mutations were prone to display such findings. Therefore, genetic testing should be performed even for patients with fluctuations in thyroid function test results to avoid misdiagnosis and inappropriate treatment.

Nephrotic syndrome (NS) is characterized by massive urinary protein leakage and associated hypoproteinemia due to increased protein permeability caused by impaired renal glomerular connections. Although there have been several sporadic reports regarding the relationship between NS and thyroid dysfunction, a consensus has yet to be reached. The mechanism of hypothyroidism in NS is attributed to the loss of protein-bound thyroid hormones, such as thyroxine-binding globulin, transthyretin, and albumin, into the urine. Herein, we report four adults with hypothyroidism that developed or worsened due to the onset of NS. The patients' underlying thyroid status was post-total thyroidectomy with supplemental levothyroxine (L-T4) in two patients, hypothyroidism with supplemental L-T4 due to Hashimoto's disease in one patient, and Hashimoto's disease with normal thyroid function in one patient. Our results suggest that the presence of a reduced thyroid reserve may predispose patients to hypothyroidism in NS. We conclude that NS may cause or exacerbate hypothyroidism. In such cases, an NS assessment, including a urine test, is required.

Many previous studies including ours have reported that athyreotic patients on levothyroxine (LT4) have relatively low serum free triiodothyronine (FT3) levels, whereas patients with large goitrous diseases often have high serum FT3 levels. Here we investigated Hashimoto thyroiditis (HT) patients on LT4 to study the relationship between thyroid volume (TV) and thyroid hormone status in hypothyroid patients on LT4. We retrospectively studied 408 euthyroid HT patients treated with LT4 for hypothyroidism; divided them as per TV and compared serum levels of free thyroxine (FT4) and FT3 and the FT3/FT4 ratio in each patient group with those in euthyroid matched control group. We also evaluated the association between serum FT3 level and FT3/FT4 ratio and TV among HT patients on LT4. In patients with TV

This study aimed to compare the quality of life (QoL) and psychological issues of patients with papillary thyroid microcarcinoma (PMC) who were under active surveillance (AS) and those who underwent immediate surgery (OP).This was a cross-sectional study conducted on 347 patients with low-risk PMC who were under AS (n = 298) or who underwent OP (n = 49). They were asked to complete two questionnaires (thyroid cancer-specific health-related QoL [THYCA-QoL] and the Hospital Anxiety and Depression Scale [HADS]). The results between the AS and OP groups were compared.The mean ages of patients in the AS and OP groups were 58.6±12.5 and 58.4±13.1 years (P =.94), respectively, and the male ratios were 34/298 (11%) and 2/49 (4.1%) (P =.14), respectively. The median follow-up periods from diagnosis in the AS and OP groups were 56.5 months (interquartile range [IQR], 32 to 88 months) and 84 months (IQR, 64 to 130 months) (P.001), respectively. In the THYCA-QoL questionnaire, the OP group had more complaints about "voice" (P.001), "psychological" (P =.025), "problems with scar" (P.001), and "gained weight" (P =.047) than the AS group. Other scales of the THYCA-QoL were comparable in the two groups. In the HADS questionnaire, the AS group had significantly better anxiety (P =.020), depression (P =.027), and total scores (P =.014) than the OP group.PMC patients in the OP group had more complaints and were more anxious and depressed than the AS group. These findings suggest that AS is a reasonable alternative to surgery for patients with low-risk PMC from the point of view of QoL and psychology.AS = active surveillance; CI = confidence interval; HADS = Hospital Anxiety and Depression Scale; LT4 = levothyroxine; OP = immediate surgery; PMC = papillary microcarcinoma; PTC = papillary thyroid carcinoma; QoL = quality of life; STAI = State-Trait Anxiety Inventory; THYCA-QoL = thyroid cancer-specific health-related quality of life; TSH = thyrotropin.

Background: Poorly differentiated thyroid carcinoma is rare and patients are typically euthyroid. We report a novel rare case of poorly differentiated thyroid carcinoma with triiodothyronine (T3) t...

Background: Some studies reported that among athyreotic patients on levothyroxine (LT4) after total thyroidectomy, patients with normal serum thyrotropin (TSH) levels had mildly low serum free triiodothyronine (fT3) levels, whereas patients with mildly suppressed serum TSH levels had normal serum fT3 levels. The reduction of the thyroid volume (TV) after radioiodine treatment for Graves' disease is well known; however, a few studies evaluated thyroidal function including serum triiodothyronine (T3) levels of hypothyroid patients on LT4 after radioiodine treatment in detail. Methods: We retrospectively studied 446 patients treated with LT4 for radioiodine-induced hypothyroidism and who had undergone ultrasonography. We compared serum fT4 and fT3 levels in hypothyroid patients on LT4 who presented an atrophic thyroid change after radioiodine treatment, with those in the euthyroid matched control group with intact thyroids. We also stratified patients with normal TSH levels according to TV and evaluated serum thyroid hormone levels. Results: In 356 of 446 (80%) patients, TV was lower than the lower limit of the 95% reference range of controls. Excluding 43 patients with high serum TSH levels, we assessed thyroid function test results in 313 patients with atrophic thyroid glands. Of these cases, eight patients with strongly suppressed TSH levels had serum fT3 levels that were significantly higher than those in controls (p

The serum free triiodothyronine (FT3)/free thyroxine (FT4) ratio in patients with huge goitrous Hashimoto’s thyroiditis (HG-HT) is relatively high. We investigated the cause of high FT3/FT4 ratios. We measured the serum FT3, FT4, and thyrotropin (TSH) levels of seven patients with HG-HT who had undergone a total thyroidectomy. Eleven patients with papillary thyroid carcinoma served as controls. The activities and mRNA levels of type 1 and type 2 iodothyronine deiodinases (D1 and D2, respectively) were measured in the thyroid tissues of HG-HT and perinodular thyroid tissues of papillary thyroid carcinoma. The TSH levels in the HG-HT group were not significantly different from those of the controls. The FT4 levels in the HG-HT group were significantly lower than those of the controls, whereas the FT3 levels and FT3/FT4 ratios were significantly higher in the HG-HT group. The FT3/FT4 ratios in the HG-HT group who had undergone total thyroidectomy and received levothyroxine therapy decreased significantly to normal values. Both the D1 and D2 activities in the thyroid tissues of the HG-HT patients were significantly higher than those of the controls. However, the mRNA levels of both D1 and D2 in the HG-HT patients’ thyroid tissues were comparable to those of the controls. Interestingly, there were significant correlations between the HG-HT patients’ D1 and D2 activities, and their thyroid gland volume or their FT3/FT4 ratios. Our results indicate that increased thyroidal D1 and D2 activities may be responsible for the higher serum FT3/FT4 ratio in patients with HG-HT.

Previous reports by us and other investigators showed that among athyreotic patients on levothyroxine (LT4) following total thyroidectomy patients with normal serum thyroid-stimulating hormone (TSH) levels had mildly low serum free triiodothyronine (FT3) levels, whereas patients with mildly suppressed serum TSH levels had normal serum FT3 levels and patients with strongly suppressed serum TSH had elevated serum FT3 levels. The objective of this study was to clarify which of these three patient groups are closer to their preoperative euthyroid condition based on reported subjective symptoms. We prospectively studied 148 consecutive euthyroid patients with papillary thyroid carcinoma who underwent a total thyroidectomy. Symptoms reflecting thyroid function documented preoperatively and following 12 months of LT4 after thyroidectomy were compared. In 65 patients with strongly suppressed TSH levels significant changes in symptoms with tendencies towards thyrotoxicosis were seen with regards to heat and cold tolerance (p < 0.01), bowel movements (p < 0.05), and hand tremors (p < 0.05). In 33 patients with normal TSH levels, significant changes in symptoms with tendencies towards hypothyroidism were seen with regards to heat and cold tolerance (p < 0.05) and activity (p < 0.05). Lastly, in 50 patients with mildly suppressed TSH levels and FT3 levels equivalent to preoperative levels, all symptom items remained equivalent to their preoperative levels. Symptoms reflecting thyroid function in patients on LT4 following total thyroidectomy suggested that patients with mildly suppressed TSH levels were closest to a euthyroid status. These data provide useful findings regarding the management of patients following total thyroidectomy.

Graves' disease (GD) may coexist with papillary thyroid microcarcinoma (PTMC). The main purpose of this study was to evaluate whether treatment with radioactive iodine (RAI) may cause acute exacerbation of PTMC concurrent with GD or not. From the medical records of 10,257 GD patients who underwent RAI therapy between 2000-2017, 12 subjects with concurrent PTMC were retrieved. Further, 49 patients with concurrent GD and PTMC who underwent no RAI administration throughout their clinical course were enrolled as controls. Size of the PTMC nodules was evaluated based on maximal diameter and tumor volume-doubling rate (TV-DR). Among the 12 subjects who underwent RAI therapy (median dose, 13 mCi), 2 showed tumors >10 mm in maximal diameter with slow growth for more than 10 years, while the other 10 showed tumors with maximal diameter ≤10 mm. No subject showed any clinical findings of nodal or distant metastasis during the follow-up periods (0.4-11.5 years) before surgery or during active surveillance. No significant differences were observed in the TV-DR values (median, 0.044/year; range, -0.81-1.40) between the study subjects and controls (median, 0.025/year; range, -0.70-1.29; p = 0.69). When comparing the TV-DR before and after RAI administration in 3 individuals in particular, in whom PTMC were cytologically confirmed before RAI administration and whose prospective follow-up data were available, tumor progression was observed to be stable or decreased after RAI administration. There were no acute exacerbations or unfavorable outcomes of concurrent PTMC and GD after low-dose RAI administration.

IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.ConclusionsAlogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Subacute thyroiditis is a self-limited inflammatory disease and very few patients undergo ultrasonographic re-examination if no nodules are found at the initial examination. The objective of the study was to assess the diagnostic accuracy of ultrasonography in detecting nodular lesions in patients with subacute thyroiditis. We conducted a longitudinal study involving 710 patients with subacute thyroiditis who underwent ultrasonographic examinations in a single center between 2008 and 2018. These examinations were performed at initial diagnosis and during follow-up, with subsequent evaluation of nodules using fine needle aspiration cytology. Ultrasonographic examination used for the initial screening of thyroid nodules in patients with subacute thyroiditis showed a sensitivity of 72.4%, specificity of 89.0%, positive predictive value of 80.4%, and negative predictive value of 83.8%. Twenty-two patients (3.1%) had concomitant papillary thyroid carcinoma, 10 of whom underwent thyroidectomy while the remaining 12 opted for active surveillance owing to having low-risk microcarcinomas. Approximately 30% of papillary carcinomas (7/22) were identified during follow-up ultrasonography, but not during the initial scan. All tumors in this false-negative group were latently localized in the bilateral hypoechoic regions of the thyroid and showed no calcified components. Of the 15 tumors that were detected during both initial and follow-up examinations, 7 exhibited calcified components and 5 were located in unaffected areas apart from the inflammatory hypoechoic region. Subacute thyroiditis highly obscures any coexisting papillary carcinoma when inflammatory hypoechoic regions are present. Ultrasonographic re-examination after a sufficient interval is indispensable for patients with subacute thyroiditis.

Background: Some investigators reported that among athyreotic patients on levothyroxine (LT4) monotherapy following total thyroidectomy, the patients with normal serum thyrotropin (TSH) levels had mildly low serum free triiodothyronine (fT3) levels, whereas the patients with mildly suppressed serum TSH levels had normal serum fT3 levels, and the patients with strongly suppressed serum TSH had elevated serum fT3 levels. The objective of the present study was to clarify which of these three patient groups is closer to their preoperative euthyroid condition. Methods: A total of 133 consecutive euthyroid patients with papillary thyroid carcinoma who underwent a total thyroidectomy were prospectively studied. The patients' serum levels of lipoproteins, sex hormone-binding globulin, and bone metabolic markers measured preoperatively were compared with the levels measured at postoperative LT4 therapy 12 months after the thyroidectomy. Results: The postoperative serum sex hormone-binding globulin (p

It is generally believed that the detection of thyroid peroxidase antibodies (TPOAb) is superior to that of thyroglobulin antibodies (TgAb) for the diagnosis of Hashimoto's thyroiditis. However, limited data are available on the comparison of TgAb and TPOAb prevalence as a diagnostic measurement for Hashimoto's thyroiditis using sensitive immunoassays. We herein used five different current immunoassay kits (A-E) to compare the prevalence of TgAb and TPOAb in Hashimoto's thyroiditis (n = 70), Graves' disease (n = 70), painless thyroiditis (n = 50), and healthy control subjects (n = 100). In patients with Hashimoto's thyroiditis, positive TgAb was significantly more frequent than positive TPOAb in kits A-D (mean ± SD of the four kits: 98.6 ± 1.7 vs 81.4 ± 2.0%). In patients with Graves' disease, TgAb prevalence was almost equivalent to that of TPOAb in five kits. Patients with painless thyroiditis exhibited positive TgAb significantly more frequently than positive TPOAb in kits A-D (73.5 ± 4.1 vs 33.0 ± 3.4%). The prevalence of TgAb alone was significantly higher than that of TPOAb alone in both Hashimoto's thyroiditis and painless thyroiditis in kits A-D. In kit E, TgAb and TPOAb prevalence did not differ significantly for any disease, and TgAb distribution was different from other kits. In conclusion, the prevalence of TgAb was higher than that of TPOAb in patients with Hashimoto's thyroiditis and painless thyroiditis using commercially available kits. We suggest that TgAb immunoassay is the first choice of screening test for thyroid autoimmune abnormalities in Japan.

While patients with large goitrous thyroid diseases often have a relatively high serum free triiodothyronine (FT3)/free thyroxine (FT4) ratio, athyreotic patients have a relatively low FT3/FT4 ratio. Here we investigated the relationship between thyroid hormone status and thyroid volume (TV) among a large number of euthyroid Hashimoto thyroiditis (HT) patients. We retrospectively enrolled 2,603 untreated HT patients who visited the Kuma hospital from 2012 to 2016, and divided them into four groups as per the TV: normal TV (

Importance Patients with chronic kidney disease have impaired vitamin D activation and elevated cardiovascular risk. Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with lower risk of all-cause mortality, regardless of parathyroid hormone levels. Objective To determine whether vitamin D receptor activators reduce cardiovascular events and mortality in patients without secondary hyperparathyroidism undergoing hemodialysis. Design, Setting, and Participants Randomized, open-label, blinded end point multicenter study of 1289 patients in 207 dialysis centers in Japan. The study included 976 patients receiving maintenance hemodialysis with serum intact parathyroid hormone levels less than or equal to 180 pg/mL. The first and last participants were enrolled on August 18, 2008, and January 26, 2011, respectively. The final date of follow-up was April 4, 2015. Interventions Treatment with 0.5 μg of oral alfacalcidol per day (intervention group; n = 495) vs treatment without vitamin D receptor activators (control group; n = 481). Main Outcomes and Measures The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up. The secondary outcome was all-cause death. Results Among 976 patients who were randomized from 108 dialysis centers, 964 patients were included in the intention-to-treat analysis (median age, 65 years; 386 women [40.0%]), and 944 (97.9%) completed the trial. During follow-up (median, 4.0 years), the primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, −1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67];P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83-1.52];P = .46). Of the 488 participants in the intervention group, 199 (40.8%) experienced serious adverse events that were classified as cardiovascular, 64 (13.1%) experienced adverse events classified as infection, and 22 (4.5%) experienced malignancy-related serious adverse events. Of 476 participants in the control group, 191 (40.1%) experienced cardiovascular-related serious adverse events, 63 (13.2%) experienced infection-related serious adverse events, and 21 (4.4%) experienced malignancy-related adverse events. Conclusions and Relevance Among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these. Trial Registration UMIN-CTR Identifier:UMIN000001194

Objective3,5,3′-triiodothyronine-predominant Graves' disease (T3-P-GD) is characterized by a persistently high serum T3 level and normal or even lower serum thyroxine (T4) level during antithyroid drug therapy. The source of this high serum T3 level has not been clarified. Our objective was to evaluate the contribution of type 1 and type 2 iodothyronine deiodinase (D1 (or DIO1) and D2 (or DIO2) respectively) in the thyroid gland to the high serum T3 level in T3-P-GD.MethodsWe measured the activity and mRNA level of both D1 and D2 in the thyroid tissues of patients with T3-P-GD (n=13) and common-type GD (CT-GD) (n=18) who had been treated with methimazole up until thyroidectomy.ResultsThyroidal D1 activity in patients with T3-P-GD (492.7±201.3 pmol/mg prot per h) was significantly higher (P3-P-GD (823.9±596.4 fmol/mg prot per h) was markedly higher (P3-P-GD and CT-GD and the serum FT3-to-FT4 ratio (r=0.370, P3-to-FT4 ratio (r=0.676, PConclusionsOur results suggest that the increment of thyroidal deiodinase activity, namely D1 and especially D2 activities, may be responsible for the higher serum FT3-to-FT4 ratio in T3-P-GD.

To assess the effects of thyroid hormone and cardiac function on senile dementia, relations between serum thyroid hormone concentrations, hemodynamic parameters and dementia rating scale scores were studied in 83 subjects aged 70 and over. Age and serum-free T3 concentrations had a significantly negative correlation in all subjects and in subjects without dementia, but not when analysed only in dementia subjects. Regarding the genesis of dementia, serum free T3 concentrations and cardiac index were both significantly lower in cerebrovascular dementia than in those without dementia. Moreover, subjects with cerebrovascular dementia showed significantly lower serum free T3 concentrations and cardiac index than those with senile dementia of Alzheimer's type in all age groups. These findings suggest that cognitive function is closely related to serum free T3 and cardiac function in subjects with cerebrovascular dementia and that serum free T3 concentrations may be a good indicator, reflecting health and cognitive status.

Some patients with massive metastatic thyroid carcinoma exhibit T(3) thyrotoxicosis. We investigated the prevalence and cause of T(3) thyrotoxicosis and the clues to the diagnosis.Serum free T(3) (FT(3)), free T(4) (FT(4)), and TSH were measured in patients with massive metastases from papillary, follicular, or medullary thyroid carcinomas (31, 20, and seven patients, respectively). Patients without recurrence served as controls. Thyrotoxic patients were reexamined 1 wk after withdrawal of levothyroxine. Type 1 and type 2 iodothyronine deiodinase (D1 and D2) activities were measured in three tumor tissues from thyrotoxic patients.The serum FT(3) level and FT(3)/FT(4) ratio in the follicular carcinoma (FC) group were significantly higher than those in the papillary carcinoma group or patients without recurrence. Four patients (20%) in the FC group but none in the other groups demonstrated T(3) thyrotoxicosis or a FT(3)/FT(4) ratio greater than 3.5. One week after withdrawal of levothyroxine, both FT(3) and FT(4) levels decreased. Retrospective measurements of FT(3) in frozen stored sera demonstrated that FT(3) exceeded the upper normal limit when FT(4) began to decrease but remained within the normal range. Tumor tissues showed high D1 and D2 activities.Twenty percent of patients with massive metastatic FC exhibited T(3) thyrotoxicosis, most likely due to increased conversion of T(4) to T(3) by tumor expressing high D1 and D2 activities. Occasional measurement of serum FT(3) in addition to FT(4) and TSH is recommended in patients with massive metastatic FC, especially when serum FT(4) decreases on fixed doses of levothyroxine.

In type 2 diabetes mellitus, there is increased risk of nephropathy and cardiovascular complications and the incidence of renal failure increases in advanced stages of the disease. Nifedipine, a dihydropyridine-type calcium antagonist, improves endothelial function in hypercholesterolemia by enhancing nitric oxide function, and increases endothelial nitric oxide bioavailability by antioxidative mechanisms. We administered nifedipine, 50 mg/day, to the hypertensive patients for 12 months. There were no other changes in any of the patient's pharmacologic regimen during nifedipine treatment. Clinical and biochemical data obtained before and after nifedipine administration were compared. All markers were measured by ELISA. The levels of platelet activation markers (CD62P, CD63, PAC-1, and Annexin V), microparticles (PDMP and MDMP), RANTES and soluble adhesion markers (sP-selectin and sVCAM-1) differed in the control group and the hypertension group. The levels of these markers were also different in hypertensive patients with and without type 2 diabetes but were unchanged in patients without diabetes in comparison to the control group. However, the concentrations of MDMPs, chemokines, and soluble adhesion markers in hypertensive patients without type 2 diabetes decreased significantly following nifedipine treatment, although the level of RANTES was unchanged. Systolic blood pressure correlated with CD62P, CD63, annexin V, and RANTES levels, and diastolic blood pressure with CD62P and annexin V levels. The effect of nifedipine on platelet activation markers and C-C chemokines in the present study indicates potential effectiveness of calcium antagonist therapy for hypertensive patients with type 2 diabetes.

Myocardial fibrosis commonly occurs in patients with end-stage renal disease (ESRD) and has proven to be an important predictor for cardiovascular events. In experimental settings, angiotensin II type 1 receptor (AT1-R) antagonists have been shown to have anti-fibrotic effects on the myocardium independent of their antihypertensive effects. In this study, to investigate whether the AT1-R antagonist losartan would have such anti-fibrotic effects in patients, we administered losartan or, for purpose of comparison, the angiotensin-converting enzyme enalapril or Ca2+-antagonist amlodipine to patients with ESRD. Thirty-nine ESRD patients with hypertension were randomly assigned to receive losartan (n=13), enalapril (n=13), or amlodipine (n=13). Ultrasonic integrated backscatter (IBS) and serological markers of collagen type I synthesis and degradation were used to assess the degree of myocardial fibrosis just before and after 6 months of treatment. There were no significant differences in antihypertensive effects among the three agents. In the enalapril- and amlodipine-treated groups, the mean calibrated IBS values increased significantly after 6 months of treatment (enalapril: -31.6 +/- 1.3 to -29.4 +/- 1.2 dB, p=0.011; amlodipine: -30.6 +/- 1.4 to -27.2 +/- 1.2 dB, p=0.012). However, the mean calibrated IBS values in the losartan-treated group did not increase after 6 months of treatment (-31.2 +/- 1.7 to -31.3 +/- 1.4 dB, p=0.88). The ratio of the serum concentration of procollagen type I carboxy-terminal peptide to the serum concentration of collagen type I pyridinoline cross-linked carboxy-terminal telopeptide was significantly reduced in the losartan-treated group (42.6 +/- 4.6 to 34.4 +/- 3.6, p=0.038). The present study indicates that losartan more effectively suppresses myocardial fibrosis in patients with ESRD than does enalapril or amlodipine despite a comparable antihypertensive effect among the three drugs.

Background: Diabetic patients also show hypercoagulability and platelet hyperaggregability, with increased levels of platelet activation-markers such as P-selectin (CD62P) and platelet-derived microparticles. We investigated the effects of losartan and simvastatin on circulating levels of platelet activation markers, microparticles, soluble selectins, and soluble cell adhesion molecules in hypertensive and hyperlipidemic patients with or without Type 2 diabetes. Methods: The subjects included 25 normotensive healthy controls and 41 hypertensive patients. The 41 hypertensive patients were divided into three groups: group A had hypertension and hyperlipidemia (n = 11), group B had hypertension and Type 2 diabetes (n = 14), and group C had hypertension, hyperlipidemia, and diabetes (n = 16). Losartan was administered to all of the patients at a dose of 50 mg/day for 24 weeks. In addition, simvastatin was administered to the hyperlipidemic patients at a dose of 10 mg/day for 24 weeks. Results: There were significant differences in the levels of CD62P, CD63, PAC-1, platelet microparticles, endothelial microparticles, sE-selectin, and sVCAM-1 between the hypertensive patients and healthy controls. These markers were all significantly increased in hypertensive and hyperlipidemic patients with Type 2 diabetes. In hypertensive patients with diabetes, CD62P, CD63, PAC-1, platelet and endothelial microparticles, and soluble adhesion markers were all decreased by losartan monotherapy. The decrease of each marker in hypertensive and hyperlipidemic patients given combined therapy with losartan plus simvastatin was greater among those with than without Type 2 diabetes. Low-density lipoprotein was decreased significantly by simvastatin and was correlated with CD62P or platelet microparticles in all of the patients. Conclusion: Administration of losartan plus simvastatin to hypertensive and hyperlipidemic patients with Type 2 diabetes may prevent the development of cardiovascular complications caused by activated platelets and microparticles via another mechanism in addition to reduction of the blood pressure or lipid levels.

S100A12, also called EN-RAGE (extracellular newly identified receptor for advanced glycation end products binding protein) or calcium-binding protein in amniotic fluid-1, is a ligand for RAGE. It has been shown that S100A12 induces adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in the vascular endothelial cell and mediates migration and activation of monocytes/macrophages through RAGE binding and that infusion of lipopolysaccharide into mice causes time-dependent increase of S100A12 in the plasma. Therefore, circulating S100A12 protein may be involved in chronic inflammation in the atherosclerotic lesion. In this study, we developed an ELISA system that uses specific monoclonal antibodies against recombinant human S100A12 to measure plasma S100A12 levels in patients with diabetes. On using our S100A12 ELISA system, the coefficients of variation of intra- and interassay were less than 4 and 9%, respectively. The analytical lower detection limit was 0.2 ng/ml. When plasma S100A12 levels were measured by this system, the concentrations were more than twice as high in the patients with diabetes, compared with those without. Using univariate analysis in all subjects, plasma S100A12 concentrations correlated with hemoglobin A1c, fasting glucose, high-sensitivity C-reactive protein and white blood cell count. Stepwise multiple regression analyses, however, revealed that only white blood cell count and hemoglobin A1c remained significant independent determinants of plasma S100A12 concentration. These results suggest that plasma S100A12 protein levels are regulated by factors related to subclinical inflammation and glucose control in patients with type 2 diabetes.

EN-RAGE is a ligand for the receptor for advanced glycation end products (RAGE) and may be involved in the development of diabetic macro- and micro-angiopathy. This study is designed to investigate the regulation of EN-RAGE gene expression in human macrophages. The amounts of EN-RAGE mRNA were measured in cultured human THP-1 macrophages after treatment with various stimuli known to modulate atherosclerosis. First, interleukin-6 (IL-6), a proinflammatory cytokine, increased the level of EN-RAGE mRNA by approximately 2-fold in a time- and a dose-dependent fashion. EN-RAGE protein was detected in the cultured medium and increased significantly by the addition of IL-6. The induction was abolished by pretreatment with the JAK kinase inhibitor and cycloheximide, but not with the MEK kinase inhibitor. Second, pioglitazone (PIO), a thiazolidinedione, decreased the level of EN-RAGE mRNA by approximately 25% of the basal in a time- and a dose-dependent fashion. Pioglitazone also inhibited the induction of EN-RAGE mRNA by IL-6. These results indicate the production of EN-RAGE is induced by IL-6 through de novo protein synthesis via the JAK-STAT kinase pathway and inhibited by the activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) in human macrophages.

Type 1 and 2 iodothyronine deiodinases (D1 and D2) catalyze thyroxine (T4) activation. In human thyroid, unlike rodents', both D1 and D2 are expressed. We have investigated the effects of thyrotropin (TSH), dibutyryl cyclic adenosine monophosphate [(Bu)2cAMP] (an activator of protein kinase A [PKA]), 12-O-tetradecanoylphorbor 13-actate (TPA) (an activator of protein kinase C [PKC]), T4, and triiodothyronine (T3) on the D2 mRNA levels and activity in cultured human thyroid cells. D2 mRNA levels were increased by TSH and (Bu)2cAMP, and the increment was faster and greater than that of D1 mRNA levels. The increment of the maximum velocity (Vmax) value for D2 by (Bu)2cAMP stimulation was similar to that of D2 mRNA levels, suggesting that (Bu)2cAMP enhances D2 activity mainly at the pretranslational level. Cycloheximide, a protein synthesis inhibitor, partially inhibited the increase of D2 mRNA levels by (BU)2cAMP, suggesting that de novo protein synthesis-dependent pathways are involved. TPA suppressed the D2 mRNA levels in the presence of (Bu)2cAMP. However, T3 and T4 did not significantly change the D2 mRNA levels and activity. In conclusion, D2 expression in human thyroid cells is more rapidly and strongly upregulated by the PKA pathway than D1 expression, and is downregulated by the PKC pathway.

SUMMARYLevels of platelet-derived microparticles (PMPs), platelet activation markers (P-selectin expressed on, or annexin V binding to, platelets (plt:P-selectin or plt:annexin V, respectively)), chemokines (IL-8, monocyte chemotactic peptide-1 (MCP-1), and regulated on activation normally T-cell expressed and secreted (RANTES)), and soluble P- and E-selectins were compared in peripheral blood from diabetic and control patients in order to develop a better understanding of their potential contribution to diabetic vascular complications. Significant increases were found for PMPs, plt:P-selectin, MCP-1, RANTES and soluble P- and E-selectins in diabetic individuals, whereas IL-8 levels were similar. Furthermore, after ticlopidine treatment, most of these factors receded to baseline levels observed in non-diabetic patients. Our findings indicate that ticlopidine might be able to prevent or reduce vascular complications in diabetic patients.

We measured serum and urinary 1,5-anhydro-D-glucitol (1,5-AG) during a glucose tolerance test (GTT) in patients with chronic renal failure (CRF) and compared the fractional excretion of 1,5-AG (FEAG) with that of diabetes mellitus (DM) patients and healthy controls. The mean serum 1,5-AG in CRF patients [60 ± 23(SE) μmol/L] was significantly lower than in controls (155 ± 7 μmol/L) in spite of a normal glycaemia. The levels in the CRF group were similar to those in the DM group. During GTT, the blood glucose profile in the CRF group was not significantly different from that of the control group, and urinary glucose excretion was negligible. However, FEAG was significantly higher in CRF patients than in controls. These data suggest that serum 1,5-AG in patients with CRF decreases due to a decrease in 1,5-AG reabsorption, independently of glucose excretion, and that serum and/or urinary 1,5-AG can be a useful marker for renal tubular dysfunction because the 1,5-AG reabsorption system is more vulnerable than the glucose reabsorption system.

We measured levels of platelet-derived microparticles (PMP), which have coagulative activity and are produced by platelet activation or physical stimulation, and CD62P/CD63-positive platelets in patients with diabetes mellitus to determine their clinical significance and effects on complications of diabetes including diabetic nephropathy. We also compared these levels before and after administration of the antiplatelet drug cilostazol. Plasma PMP and CD62P/CD63-positive platelet levels were significantly higher in patients with diabetes mellitus than normal controls. CD62P-positive platelet levels were significantly higher in patients with nephropathy than in patients without complications. After administration of cilostazol, PMP and CD62P/CD63-positive platelet levels were significantly decreased. The increases in platelet activity and its related procoagulant activity appear to account in part for the hypercoagulability observed in diabetes mellitus. Our findings suggest that activated platelets might play a role in the development of diabetic nephropathy. Furthermore, antiplatelet therapy with cilostazol for diabetic patients may be useful as antithrombin therapy including antiplatelet therapy, since it suppresses the production of intrinsic coagulants produced by platelet activation.

The present study was undertaken to evaluate thyroid function and thyrotropic action of hCG in multiple pregnancy. We examined serum samples from 9 multiple pregnant women (3 triplets and 6 twins) and 27 singleton pregnant women as control subjects. Serum hCG levels in multiple pregnancy were higher than those in singleton pregnancy in the second and third trimesters (P < 0.01). The mean free T3 and T4 concentrations in multiple pregnancy did not differ from those in singleton pregnancy in each trimester. Serum hCG levels showed a statistically significant positive correlation with free T3 and T4 levels in singleton pregnancy (P < 0.001). However, these correlations were not observed in multiple pregnancy. Thyroid stimulation activity (TSA) determined by cAMP accumulation in FRTL-5 cells in multiple pregnancy sera was significantly higher than that in singleton pregnancy in the first trimester (P < 0.05), but did not differ in the second and third trimesters. Moreover, TSA did not show any correlation with serum hCG levels in multiple pregnancy in contrast with the results in normal pregnancy. A bioactivity/immunoreactivity ratio of hCG in multiple pregnancy was lower than in singleton pregnancy in the second and third trimesters. The discrepancy between immunoreactivity and thyrotropic activity of hCG may be caused by the variable thyrotropic potency of heterogeneous hCG molecules in multiple pregnancy.

To evaluate the regulatory mechanism of human Type 1 iodothyronine deiodinase (D1) gene expression, we measured the D1 mRNA levels in peripheral blood mononuclear cells (PBMC) in normal control subjects and in patients with Graves' disease. We used competitive reverse transcriptase-polymerase chain reaction with the deleted complimentary RNA of D1 as the standard for quantification. The D1 mRNA levels in PBMC were increased significantly in patients with Graves' disease compared with that in normal controls. There was a significant (p < 0.01) positive correlation (r=0.698) between D1 mRNA level and serum T3 concentration. When PBMC from the normal volunteers were cultured with various doses of T3, the quantity of D1 mRNA increased significantly in a dose-dependent manner. These findings indicate that PBMC D1 mRNA is actually up-regulated by T3in vivo,and we postulate that a vicious spiral of increasing T3 and D1 is responsible for the exacerbation of thyrotoxicosis in hyperthyroid Graves' disease.

Some occult thyroid carcinomas are hypothesized to regress and be eventually obliterated. We report here a patient whose condition supports this hypothesis. A 51-year-old male with primary hypothyroidism due to Hashimoto's thyroiditis suffered from a rib bone tumor. He had a diffuse goiter with no nodular lesion. Serum FT4 and TSH concentrations were 0.8 ng/dl and 36.4 microU/ml on taking 100 microg/day of T4. Anti-Tg- and -TPO-Ab were strongly positive (99 and 1380 U/ml). The iodine 123 scintigraphy demonstrated clear accumulation in the rib tumor, whereas the thyroid was scarcely visible. Biopsy of the rib tumor showed papillary proliferation of large atypical cells, which were immunohistochemically positive for thyroglobulin. Metastatic bone tumor of papillary thyroid carcinoma was therefore strongly suspected. He underwent a total thyroidectomy and the thyroid was stepwise sectioned completely at 3 mm intervals. The thyroid condition was diagnosed as Hashimoto's thyroiditis demonstrating diffuse and dense fibrosis, lymphocyte infiltration with lymphoid follicles and flattened atrophied follicles, but no carcinomatous foci were found. He was treated with I-131 and scintigraphy after the ingestion showed distinct accumulation in the rib tumors similar to that before thyroidectomy. No other abnormal uptake was observed. It is suggested that the primary occult thyroid papillary carcinoma regressed and was obliterated possibly by some immunologic or other host-resistance factors after it metastasized to the distant bone.

As we had an opportunity to take blood samples from a totally thyroidectomized patient who had attempted suicide by taking 2,000 microg of Levothyroxine (L-T4), the serum levels of thyroid hormones were sequentially measured to investigate the metabolism of circulating thyroid hormones in an athyreotic human. The serum concentrations of most thyroid hormones reached a peak on the second day, but the serum T3 level showed a peak one day later. The maximum concentrations of T4 (315 microg/l), FT4 (48.8 ng/l) and rT3 (0.80 microg/l) were very high, while the peak T3 level (1.92 microg/l) did not exceed the upper limit of the normal range. The serum T4 and rT3 levels returned to their normal range 13-17 days after the suicide attempt. The TSH level was suppressed rapidly and reached its nadir (0.044 mU/l) on the 6th day. During this period, the T1/2 and MCR of serum T4 were 10.4 days and 0.64 l/day, respectively, which values were almost equivalent to those observed during 15 days after discontinuation of the maintenance L-T4 therapy. In summary, the oral intake of a large amount of L-T4 at one time does not induce a proportional increase in the T3 level in an athyreotic person. The MCR of serum T4 is decreased and the T1/2 of serum T4 is prolonged, probably due to the lack of intrathyroidal deiodination. These findings support the conclusion that the D1 activity in the thyroid is one of the major determinants in the metabolic clearance of serum T4.

We report a 62-year-old male patient who had variant angina and isolated adrenocorticotropic hormone(ACTH) deficiency. His serum sodium concentration was low and vasopressin was inappropriately high for the low plasma osmolality. Serum free thyroxine (FT4) was low and thyroid stimulating hormone (TSH) was high with positive anti-thyroperoxidase antibodies, compatible with Hashimoto's thyroiditis. Treatment with Amrodipine and hydrocortisone relieved chest symptoms and hyponatremia, and hypothyroidism was also normalized. It is suggested that coronary artery spasm may be related to cortisol deficiency and/or inappropriately high vasopressin secretion and that hypothyroidism was ameliorated because the reduced responsiveness to TSH returned to normal due to hydrocortisone supplement.(Internal Medicine 37: 398-402, 1998)

It is well known that human chorionic gonadotropin (hCG) is sometimes secreted from nontrophoblastic neoplasms. To elucidate the role of ectopic hCG, we investigated the effect of hCG produced from a papillary thyroid cancer cell line (B-CPAP cells) on stimulation and growth promotion of FRTL-5 rat thyroid cells. Ectopic hCG contained in the culture medium of B-CPAP cells was purified using gel filtration and bioassayed for thyrotropic activity in FRTL-5 cells. Addition of ectopic hCG (up to 5.2 x 10(4) IU/L) increased cyclic adenosine monophosphate (cAMP) accumulation and 3H-thymidine incorporation in FRTL-5 cells dose dependently. These effects were almost as potent as the stimulation induced by standard hCG CR-127. After the absorption of the ectopic hCG by anti-hCG-beta monoclonal antibody, the cAMP accumulation was significantly decreased. Analysis of ectopic hCG isoforms with different isoelectric points indicated the predominance of the acidic hCG isoform with isoelectric point (pI) 3.8-3.2 that is the major isoform of standard hCG. Basic isoforms (pI 5.7-5.3) with higher thyrotropic potency were also detected. These results indicate that the ectopic hCG secreted from papillary thyroid cancer cells possess intrinsic thyroid-stimulating and growth-promoting activity. The ectopic hCG may act as an autocrine-paracrine factor in nontrophoblastic neoplasms.

Human thyroid xenografts and the autologous bone marrow (BM) cells from five patients with Graves' disease (GD) were simultaneously xenografted into severe combined immunodeficient (SCID) mice to study the role of BM cells for the perpetuation of human GD autoimmunity and hyperthyroidism. All SCID mice engrafted with thyroid tissue (TH) alone, TH+autologous peripheral blood mononuclear cells, and TH+autologous BM cells produced similar amounts of human IgG; however, the production in TH+BM-engrafted mice peaked later than that of mice without BM. Production of thyroperoxidase antibody and thyroglobulin antibody in TH+BM-bearing SCID mice peaked in later weeks after xenografting than in those without BM. Moreover, human Graves' hyperthyroidism was actually reconstituted in TH+BM-transplanted mice; this was confirmed by (A) significantly higher levels and longer periods of secreting thyroid-stimulating antibody than those in mice without BM engraftment, (B) persistent hyperthyroxinemia up to the end of the experiment, (C) extremely high radioiodine uptake of the xenografted thyroid tissue, and (D) histological findings of the maintenance of hyperplastic change of the xenografted thyroid epithelial cells. Human BM stem cells (CD34) were identified only in mice with TH+BM xenografts when analyzed by immunohistochemistry. In conclusion, (A) we have developed an animal model for human hyperthyroid GD by simultaneous xenotransplantation of GD thyroid tissue plus autologous BM cells into SCID mice, and (B) BM cells have a crucial role for perpetuating human GD autoimmunity and hyperthyroidism in this system. European Journal of Endocrinology 136 213–222

To investigate the effect of adding a surfeit of CD8+ T cells as a potential immunoregulator in Graves' disease (GD), thyroid tissues from 4 patients with GD and 2 normal subjects (N) were initially xenografted into nude mice. Eight weeks after xenografting, the thyroid tissues, which were then devoid of lymphocytes and appeared normal, were retrieved from the nude mouse, and rexenografted (rexenografts) into severe combined immuno-deficient (SCID) mice; 20 x 10(6) of autologous peripheral blood mononuclear cells (PMBC) or 20 x 10(6) of CD8(+)-depleted PBMC ("non-CD8 cells," i.e., CD4-enriched PBMC) were simultaneously engrafted into SCID mice with thyroid rexenografts. In addition, 20 x 10(6) of CD8(+)-enriched PBMC ("CD8-doubled" cells, which were prepared to double the percentage of CD8+ T cells compared to that of PBMC) were engrafted into SCID mice with rexenografts from 2 GD and 2 N; finally, 20 x 10(6) of PBMC plus an extra 10 x 10(6) of CD8+ T cells ("extra-CD8 added" cells, total 30 x 10(6) of CD8-enriched cells) were engrafted into separate SCID mice with rexenografts from 2 GD. The reengraftment of GD rexenografts or N rexenografts alone did not result in the detection of thyroperoxidase (TPO)-antibodies (Abs), thyroglobulin (Tg)-Abs, thyroid-stimulating Ab (TSAb) production, human IgG, or lymphocytic infiltration in the xenografts. However, the engraftment of either autologous PBMC or non-CD8 cells from patients with GD and N into SCID mice with rexenografts caused human IgG to become detectable and then rise further in 10 of 17 SCID mice; when human IgG, TPO-Ab, Tg-Ab, and TSAb were quantitated, GD rexenografts plus non-CD8 cells engrafted into SCID mice showed a higher production of each antibody and human IgG than in GD rexenografts plus PBMC, or GD rexenografts plus CD8-doubled cells, or GD rexenografts plus extra "CD8-added" cells. Moreover, when CD8-doubled cells or extra CD8-added cells with rexenografts were engrafted to SCID mice with rexenografts, they showed generally lower production of human IgG and thyroid antibodies compared to SCID mice into which PBMC were engrafted with rexenografts, despite the fact that 50% more cells (30 x 10(6)) were engrafted in the preparations of extra CD8-added cells. In conclusion, CD8+ T cells from patients with GD appeared to suppress the induction of thyroid antibodies, TSAb, and human IgG. The CD8+ cells thus are acting as suppressor or regulatory T cells. Such cells might be important in the pathogenesis of autoimmune thyroid disease.

We studied the effects of exogenous human IFN-gamma or neutralizing monoclonal antibody (mAb) to IFN-gamma on xenografted human Graves' thyroid tissue in severe combined immunodeficient (SCID) mice to investigate a possible role of IFN-gamma in the pathogenesis of human Graves' disease. Human thyroid tissues from four patients with Graves' disease were xenografted into SCID mice. Two weeks after xenografting, mice were divided into three groups with human IgG levels similar to each other. Mice in the first group were treated with human IFN-gamma daily for 6 weeks; mice in the second (similar) group were treated with an mAb to IFN-gamma; mice in the third group were given mouse IgG only (control group). Blood samples were taken every 2 weeks for human IgG and thyroid-specific autoantibodies (Tg-Ab, TPO-Ab, and thyroid-stimulating antibody). After 6 weeks' treatment, mice were killed, and the thyroid xenograft was examined for thyrocyte HLA-DR expression. Human IgGs were produced equally in all three groups; mice treated with IFN-gamma showed significantly lower amounts of thyroid autoantibodies than those in the control group. Thyrocyte HLA-DR expression was markedly increased in xenografts from mice with IFN-gamma administration. On the other hand, anti-IFN-gamma mAb injection caused only slight suppression of HLA-DR expression on xenografted thyroid cells. In conclusion, IFN-gamma may down-regulate the production of thyroid-specific autoantibodies but not human IgG, at least under these circumstances; there thus may be specific inhibitory effects of IFN-gamma against thyroid-specific autoantibody production of intrathyroidal plasma cells, and this animal model may help to elucidate the possible role of cytokines in the pathogenesis of Graves' disease.

The pathogenesis of Graves' ophthalmopathy (GO) is still unclear and the possible role of TSH receptor antibody in the development of GO is controversial. However, the recent availability of severe combined immunodeficient (SCID) mice has provided a means to study of human autoimmune thyroid disease in an in vivo environment. In the present study, we xenografted human retroorbital (RO) tissues from 9 patients with GO into 9 SCID mice and the autologous peripheral blood mononuclear cells (PBMC) from 5 of 9 GO patients were engrafted into 5 separate SCID mice to reconstitute the immunological environment of human GO. Mice blood samples were taken every 2 weeks for the measurements of human IgG, thyroglobulin antibody (Tg-Ab), thyroperoxidase (TPO)-Ab, thyroid-stimulating antibody (TSAb), and interferon-gamma (IFN-gamma). Eight weeks after xenografting, mice were killed; RO tissues were analyzed histologically, SCID mice with RO tissues from 2 of 9 GO patients produced human IgG peaking at 6-8 weeks after xenografting. TPO-Abs and TG-Abs were detectable in low titer in mice with RO tissue xenografts from 3/9 and 4/9 GO patients, respectively. The mean level of IFN-gamma in SCID mice with GO RO xenografts was higher than that of a control subject (RO tissue from a non-GO patient). TSAbs were actually produced from 7 of 9 mice xenografted with GO RO tissues, and reached their peaks at 2-8 weeks after xenografting; autologous PBMC (alone, without RO tissues)-engrafted SCID mice did not produce any detectable level of TSAb. The control mouse did not produce any detectable levels of human IgG, TPO-Ab, Tg-Ab, or TSAb. Immunohistochemical analysis of orbital mononuclear cell infiltrates revealed a predominance of T lymphocytes, with a small percentage of B lymphocytes in GO RO tissue graft. In conclusion, we have successfully reconstituted the SCID mice with human lymphocytes of RO tissues from patients with GO. Autoreactive B cell clones responsible for secreting TSAb exist in GO RO tissue and may be a key factor in the initiation and/or the progression of GO.

Various drugs may cause thyroid dysfunction. The drugs which may cause thyrotoxicosis include interferon, molecular-targeted agents, amiodarone, thyroid hormone itself and so on. Those which cause hypothyroidism include anti-thyroid drugs, lithium and iodine etc. which inhibit thyroid hormone synthesis and secretion, and dopamine etc. which block TSH secretion. Those drugs which alter the thyroid hormone metabolism or the binding to TBG or those inhibit thyroid hormone absorption may cause hypothyroidism or deteriorate it in patients with hypothyroidism treated with thyroid hormone or those with diminished reserved capacity. When thyroid dysfunction occurred, it is better to discontinue the causative drug, but in many cases, the patients are forced to be treated with the drug being continued.

To evaluate the role of CD45 (especially that of the ectodomain region B) on immunocyte-thyrocyte signaling in patients with autoimmune thyroid disease (AITD), we have examined the in vitro and in vivo effects of a monoclonal antibody (mAb) against with CD45RB, termed MT3. MT3 was added to cultured peripheral blood mononuclear cells (PBMC) from patients with AITD and was additionally injected into severe combined immunodeficient (SCID) mice to which Graves' thyroid cells and intrathyroidal lymphocytes were engrafted. MT3 stimulated proliferation of PBMC when cultured for 2 to 3 days in patients with Hashimoto's thyroiditis (HT) and Graves' disease (GD) and in normal controls (NC). However, when cultured for 7 days, the stimulation index [SI: counts per minute (cpm) with mAb/cpm without mAb] was lowered by MT3 in NC and GD patients. However, the mean SI was not lowered in patients with HT. In SCID mice, the concentrations of human immunoglobulin G, antithyroglobulin and antithyroperoxidase antibodies in sera were not significantly changed by injecting MT3. The expression of human leukocyte antigen (HLA)-DR and intercellular adhesion molecule (ICAM)-1 on engrafted human thyrocytes decreased after the tissues were engrafted into the control mice to which vehicle alone was injected. However, in the mice injected with MT3, HLA-DR and ICAM-1 expression remained high or up-regulated by the injection.(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate the cause(s) of central hypothyroidism with normal or elevated TSH concentrations, we evaluated the bioactivity of serum TSH as well as pituitary and thyroid function. Seven hypothyroid patients had documented deficiencies of anterior pituitary hormones other than TSH. Basal TSH concentrations ranged from 2.2-14.8 microU/mL. Six patients had low T4 and free T4 concentrations; the remaining patient had a low free T4 and a low normal T4 level with an elevated TSH concentration of 14.4 microU/mL. The mean increment in TSH 30, 60, and 90 min after TRH administration (mean delta TSH) in these patients was 13.5 +/- 9.1 microU/mL (mean +/- SD), which was not significantly different from the value in controls (9.2 +/- 3.5 microU/mL). However, the ratio of the T3 increment at 120 min (delta T3) to mean delta TSH (delta T3/mean delta TSH) in patients was 53.9 +/- 29.3 ng/microU, significantly lower than the control value of 239.5 +/- 97.5 ng/microU (P0.01), suggesting that the thyroid response to endogenous TSH was blunted. The serum T4 concentration correlated with the mean delta TSH in these patients (r = 0.78; P0.05), suggesting that hypothyroidism is dependent on conserved pituitary function. The mean bioactivity to immunoreactivity ratio of basal TSH in patients was 0.97 +/- 0.27 and was not significantly different from the normal value of 1.05 +/- 0.22. One of the two patients with high basal TSH (10 microU/mL) had a ratio of 0.59, which is just below the mean +/- SD of normal subjects (0.61), suggesting that most patients had normal TSH bioactivity in vitro. Our findings suggest that in vivo bioactivity of TSH is decreased because of a pituitary disorder, but in vitro bioactivity of TSH is variable in patients with central hypothyroidism.

Nine patients with Graves' ophthalmopathy (GO) were treated with intravenous methylprednisolone pulse therapy and followed up by ophthalmological assessment, magnetic resonance imaging, and thyroid-associated autoantibody (thyroid stimulating antibody (TSAb), TSH binding inhibitor immunoglobulins (TBII), and anti-eye muscle antibody (EMAb)). Ophthalmological assessment was performed by the ophthalmopathy index (OI) which was made on the basis of the system recommended by the American Thyroid Association Committee. EMAb was expressed as the ratio of density of the 64 kDa band of eye muscle membrane to that of 92 kDa non-specific band found with all normal sera when assessed by western blotting. Five patients with mild ophthalmopathy (OI4) did not show progressive improvement in OI. Three of 4 patients with severe eye disease (OI4) showed a progressive and distinct improvement in OI. These 3 patients had high TSAb levels before methylprednisolone pulse therapy. One patient with severe ophthalmopathy did not respond to this pulse therapy; this patient's TSAb was negative. A significant positive correlation was observed between the activity of TSAb before treatment and the improvement in OI (delta OI) (r = 0.86, P0.01, n = 9). The relationship between delta OI and EMAb did not reach significance. These results suggest that TSAb in sera of GO patients can be a useful marker for predicting the efficacy of methylprednisolone pulse therapy.

Resveratrol is known to improve endothelial function in animals, but little is known about its effect on human subjects. Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors underlying endothelial dysfunction. We hypothesized that the modified resveratrol, Longevinex, improves endothelial function in patients with MetS. Thirty-four patients who had been treated for MetS and lifestyle-related disease were randomly assigned to group A, in which Longevinex was administered for 3 months and then discontinued for 3 months, whereas in the time-matched group B, Longevinex was administered between 3 and 6 months. These 2 groups of patients received similar drugs at baseline for diabetes mellitus, dyslipidemia, or hypertension. Flow-mediated dilatation significantly increased during the administration of Longevinex but decreased to baseline 3 months after the discontinuation of Longevinex in the group A patients. Conversely, in the group B patients, flow-mediated dilatation remained unchanged for the first 3 months without Longevinex but was significantly increased 3 months after the treatment with Longevinex. Longevinex did not significantly affect blood pressure, insulin resistance, the lipid profile or inflammatory markers during 6-month follow-up. These results demonstrate that Longevinex specifically improves endothelial function in subjects with MetS who were receiving standard therapy for lifestyle-related disease.

In hemodialysis (HD) patients, obesity has been recognized as a serious risk factor for mortality and morbidity for cardiovascular diseases. In addition, abnormalities of lipid profiles exist in these patients. In patients undergoing maintenance HD, incidences of abnormality of lipid profiles and visceral obesity determined by computed tomography scans were compared. In addition, the relationship between visceral fat area (VFA) and brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, or carotid intima-media thickness (IMT), an index of atherosis, was examined. The incidence of high VFA (27.0%) was significantly greater than that of high body mass index (BMI) (9.7%), high low-density-lipoprotein cholesterol (LDL-C) (4.8%), and high triglyceride (12.7%). In patients with diabetes mellitus (DM), waist circumference and VFA showed a significant positive relationship with baPWV. baPWV was significantly higher in patients with high VFA and DM than in patients with low VFA without DM, those with high VFA without DM, and those with low VFA and DM. Carotid IMT was significantly greater in patients with high VFA and DM than in those with low VFA without DM and those with low VFA and DM. The incidence of high VFA was much greater than that of high BMI, high LDL-C, or high triglyceride. Visceral fat accumulation may be related to both arterial stiffness and atherosis in diabetic patients on maintenance HD.

Type 2 diabetes mellitus (T2DM) associated with metabolic syndrome (MetS) represents a high risk of cardiovascular disease. We compared the effect of early intervention with pioglitazone versus voglibose on physical and metabolic profiles and serum adiponectin level in patients with T2DM associated with MetS. Sixty patients who were diagnosed for the first time as T2DM associated with MetS were analyzed for insulin sensitivity, lipid profile, serum adiponectin and systemic inflammation. Those patients were randomly assigned to oral pioglitazone group (n = 30) or voglibose group (n = 30) in addition to conventional diet and exercise training. Body mass index and waist circumference did not change in the pioglitazone group, whereas these physical parameters significantly decreased in the voglibose group during a 6-month follow-up period. However, glycosylated hemoglobin, fasting plasma glucose, and HOMA-IR more significantly decreased in the pioglitazone group. The level of serum adiponectin especially high-molecular weight adiponectin markedly increased in the pioglitazone group. Moreover, high sensitive CRP significantly decreased only in the pioglitazone group. These results suggest that voglibose is superior in improving obesity, while pioglitazone is superior in ameliorating insulin sensitivity and increasing serum adiponectin in patients with an early stage of T2DM associated with MetS.

Type 2 iodothyronine deiodinase (D2) is an enzyme that catalyzes the production of triiodothyronine (T3) from thyroxine (T4) and plays a critical role in providing the local intracellular T3. Although D2 is highly expressed in brown adipose tissue, it was thought that D2 is hardly expressed in white adipose tissue. In the present study, we examined whether D2 is expressed in human preadipocytes, using human mesenteric and subcutaneous preadipocytes (HMPA and HSCPA, respectively).HMPA and HSCPA were purchased and cultured in the preadipocyte medium containing 10% fetal bovine serum. We measured D2 activity and mRNA level in HMPA and HSCPA incubated with or without dibutyryl cyclic adenosine monophosphate [(Bu)₂cAMP].D2 activity and mRNA were detectable in human HMPA and HSCPA. The apparent Michaelis-Menten constant (K(m)) value for T4 in HMPA was 2.1 ± 0.2 nM, and the maximum velocity (V(max)) value was 333.3 ± 28.0 femtomols of I⁻ released/mg protein/hour, respectively. On the other hand, the apparent K(m) value for T4 in HSCPA was 2.0 ± 0.2 nM and the V(max) value was 91.2 ± 8.7 femtomols of I⁻ released/mg protein/hour, respectively. D2 activities in HMPA and HSCPA incubated with 1 mM (Bu)₂cAMP for 24 hours were 7-fold (HMPA) and 3-fold (HSCPA) higher than those without (Bu)₂cAMP, respectively. D2 mRNA levels in HMPA and HSCPA incubated with 1 mM (Bu)₂cAMP for 3 hours were 10-fold (HMPA) and 5-fold (HSCPA) higher than those without (Bu)₂cAMP, respectively.In the present study, we have clearly demonstrated that D2 activity and mRNA are present in the human preadipocytes from both mesenteric and subcutaneous adipose tissue. Our experiments are the first ones that identify human preadipocytes as one of the sources of T3 production.

To evaluate the relationship between eye changes and autoantibody to the thyrotropin receptor in patients with Graves' disease, we evaluated the eye changes using magnetic resonance imaging and the results were correlated with thyroid-stimulating antibody, thyrotropin binding inhibitor immunoglobulin and thyroid growth activity. Subjects were 15 patients with Graves' disease who had Graves' ophthalmopathy, including exophthalmos and other signs and symptoms, and nine patients without ophthalmopathy; all were maintained in a euthyroid state by antithyroid drugs. The thyrotropin-binding inhibitor imunoglobulin was measured by a kit, and thyroid-stimulating antibody and thyroid growth activity were evaluated by cyclic adenosine 3′,5′-monophosphate production and [3H]thymidine incorporation, respectively, by cultured functional rat thyroid lined cells. The sum of the swelling ratios (muscle thickness to the diameter of the optic nerve) of the four extraocular muscles correlated well with the degree of exophthalmos. The thyrotropin-binding inhibitor immunoglobulin was positive in nine out of 15 patients with ophthalmopathy; however, no correlation was observed between the activity and exophthalmos or muscle swelling. No significant correlation was observed between muscle changes and thyroid growth activity either. On the other hand, thyroid-stimulating antibody (642±91%) in Graves' patients with ophthalmopathy was significantly (p

To investigate the peripheral metabolic status during normal pregnancy, we measured the number of erythrocyte Na,K-ATPase units as well as the cation transport activity of the pump from 32 normal pregnant women and 12 normal controls. The number of pump units determined by maximal ouabain binding to erythrocyte in normal pregnancy was significantly higher than that in normal controls (mean +/- SEM: 0.52 +/- 0.03 vs. 0.39 +/- 0.04 pmol/10(9)RBC, P0.05). The total cation transport activity of the pump measured by 86Rb uptake also significantly increased during pregnancy (98.9 +/- 6.4 vs. 73.1 +/- 5.4 nmol/10(9) RBC, P0.01). However, the mean cation transport activity per pump unit, which was presumed to be an indicator of the peripheral metabolic status, was unchanged in any of three trimesters when compared with that in normal controls. Serum FT4 levels measured by two different methods were significantly lower in the third trimester than in the first trimester (P0.01). In conclusion, erythrocyte Na, K-ATPase activity per pump unit is normal in pregnant women, suggesting that the peripheral metabolic status in pregnancy seems to be normal. Increases in both the number and function of the pump may be influenced by factors other than thyroid function.