We propose a new classification of thyroid follicular cell tumors which is correlated with patient’s prognosis. It is unique as to two new categories: borderline malignancy between benign and malignant, and moderately differentiated adenocarcinoma (MDA) as a differentiation classification to stratify tumor aggressiveness. As to diagnostic criteria, we recommend invasiveness (capsular and vascular invasion) to separate benign and malignant and it should not be based on presence or absence of papillary thyroid carcinoma (PTC) type nuclear features (PTC-N). Thus borderline malignancy in our new classification includes some of the formerly malignant tumors and they are 1) papillary microcarcinoma, 2) encapsulated conventional PTC (EncPTC), 3) encapsulated follicular variant PTC (EnFVPTC), 4) well differentiated tumor of uncertain malignant potential (WDT-UMP), 5) follicular tumors of uncertain malignant potential (FT-UMP), and 6) capsular invasion only follicular thyroid carcinoma (FTC). Review of the literature revealed that those thyroid tumors have consistently excellent outcome. Well differentiated follicular cell adenocarcinoma (WDA) in our classification includes common type PTC and low-risk follicular carcinoma (FTC). They are invasive (diffuse infiltrative) common type PTC and minimally invasive type FTC with less than 4 foci of angioinvasion. Moderately differentiated follicular cell adenocarcinoma (MDA) includes FTC with angioinvasion (more than 4), aggressive variants of PTC, such as tall cell, columnar cell, solid, loss of cellular polarity/cohesiveness (hobnail) variants and encapsulated carcinoma with high grade histology. Poorly differentiated carcinoma (PDC) includes PDC of WHO definition, insular carcinoma, tumors with minor anaplastic transformation and tumors with distant metastasis at presentation.

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Toxic adenoma and toxic multinodular goiter (TMNG) are common causes of hyperthyroidism in iodine-deficient regions, but they are relatively rare in iodine-sufficient regions, including Japan. Constitutive activating mutations of the thyroid stimulating hormone receptor (TSHR) gene and adenylate cyclase-stimulating G α protein (GNAS) gene are frequent in these thyrotoxic disorders. Here we report two cases of rare TSHR gene mutations in Japanese thyrotoxicosis patients. In Case 1, we observed multiple toxic nodules with thyrotoxicosis, and in Case 2, we detected a solitary toxic nodule in an 8-year-old girl. In both cases, ultrasonography showed thyroid nodules and scintigraphy revealed increased uptake. Total thyroidectomy was performed for Case 1 and a hemi-thyroidectomy was performed for Case 2. Genetic analysis of the resected tissues revealed an I568F mutation in Case 1 and a S281I mutation in the TSHR gene in Case 2. The I568F mutation was located in the second extracellular loop, and the S281I mutation was located in the N-terminal extracellular domain of the TSH receptor. In Case 1, the mutation was restricted to the largest nodule, and was not detected in other functioning nodules or non-nodule thyroid tissue. Bi-allelic expression of the TSHR gene was confirmed by reverse transcription-polymerase chain reaction in both tumors. Both the I568F and S281I mutations were studied previously in vitro, and were revealed to cause basal activation of the protein kinase A pathway. Case 1 represents the second reported case of an I568F mutation and Case 2 represents the third reported case of an S281I mutation.

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We aimed to evaluate plasma plasminogen activator inhibitor-1 (PAI-1) antigen levels in women with polycystic ovary syndrome (PCOS) and different levels of adiposity and PCOS phenotypes. We studied 199 women with PCOS and 50 age-matched healthy women divided in normal weight (n=100 and n=25, respectively) and overweight/obese (n=99 and n=25, respectively). Normal weight and overweight/obese patients with PCOS were further divided in patients diagnosed according to the 1990 criteria (i.e. with anovulation and hyperandrogenemia; 1990 criteria group) and in patients with the additional phenotypes introduced in 2003 (i.e. with polycystic ovaries and either anovulation or hyperandrogenemia; additional 2003 criteria group). In normal weight subjects, plasma PAI-1 levels did not differ between women with PCOS (regardless of group) and controls, or between the 1990 criteria and the additional 2003 criteria groups of PCOS. In overweight/obese subjects, plasma PAI-1 levels were higher in both the 1990 criteria and the additional 2003 criteria groups of PCOS compared with controls (p<0.001 and p=0.004, respectively), but did not differ between the 1990 criteria and the additional 2003 criteria groups of PCOS. In conclusion, plasma PAI-1 levels are elevated in overweight/obese women with PCOS but not in normal weight women with this syndrome. Plasma PAI-1 levels do not differ between the phenotypes of PCOS.

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Sleep-disordered breathing (SDB), especially sleep apnea-hypopnea syndrome (SAS), is often observed in patients with active acromegaly. This complication is a risk factor for cardiovascular disease and associated with increased morbidity and mortality in acromegaly. However there is little information on SDB in Japanese patients with acromegaly. We investigated the prevalence of SDB and association between the severity of SDB and various features and biomarkers in Japanese patients with acromegaly. Twenty-four Japanese patients with active acromegaly underwent overnight cardiorespiratory monitoring, hormonal assays and cephalometric measurements on X-ray. A high prevalence of SDB was detected in acromegaly (87.5%). Log apnea-hypopnea index (AHI) correlated positively with soft palate length / body height (X-ray) (r=0.44, p=0.043), but not with log growth hormone levels and insulin-like growth factor type-1 standard deviation scores, size of pituitary adenoma, disease duration, body mass index, waist circumference, estimated visceral fat area, heel pad thickness / height, tongue thickness/ height, or oropharyngeal dimension/ height. In conclusion, our study demonstrated a high prevalence of SDB in Japanese patients with acromegaly, and its severity correlated with soft palate length. Based on the high incidence of SDB identified in the present study, we recommend that all patients with acromegaly are routinely screened for SDB for early diagnosis and treatment.

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The goal of the study was to examine the association of subcutaneous and visceral fat mass with serum concentrations of adipokines in 130 subjects with type 2 diabetes mellitus. The levels of serum high sensitivity C-reactive protein (HS-CRP), adiponectin, high-molecular-weight (HMW) adiponectin, interleukin-18, and retinol-binding protein 4 were measured. Percentage body fat was determined by dual energy X-ray absorptiometry, and subcutaneous and visceral fat areas were measured by abdominal CT. HS-CRP had significant positive correlations with percentage body fat and subcutaneous fat area, and a particularly significant positive correlation with visceral fat area. Serum adiponectin had a negative correlation with the subcutaneous and visceral fat areas, with the strongest correlation with the visceral fat area. Similar results were obtained for HMW adiponectin. Serum adiponectin had a negative correlation with visceral fat area in subjects with a visceral fat area < 100 cm², but not in those with a visceral fat area ≥ 100 cm². In contrast, serum HS-CRP showed a positive correlation with visceral fat area in subjects with visceral fat area ≥ 100 cm², but not in those with a visceral fat area < 100 cm². These findings indicate that an increased visceral fat area is associated with inflammatory changes, and that inflammatory reactions may alter the functional properties of visceral fat in type 2 diabetes mellitus.

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Goiter is a very common clinical problem; however, Langerhans cell histiocytosis (LCH) with thyroid involvement that presents as a goiter is very rare. In this article, we report one case of thyroid LCH. An 18-year-old male patient presented with goiter, polyuria, polydipsia, and lymphadenectasis of the neck, and LCH was confirmed by a lymph node biopsy and pathological investigation. Without a thyroidectomy, the goiter shrank after nine cycles of chemotherapy. In addition, we summarize the reported thyroid LCH cases in the literature from the last 10 years. LCH usually involves other organs, such as the lungs, bones, skin, pituitary gland, and lymph nodes. Thyroid LCH is more common in adults than in children, and it may coexist with a thyroid carcinoma. Without any unique thyroid manifestations, either clinically or by imaging, it is difficult to distinguish thyroid LCH from other thyroid diseases. Pathology is the gold standard for the diagnosis of LCH. A fine needle aspiration biopsy (FNAB) may help to diagnosis LCH, although sometimes it leads to misdiagnosis. Chemotherapy is recommended for multi-system LCH. Younger patients with widespread disease or who are non-responsive to chemotherapy have poor outcomes.

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The aim of this study was to assess the changes in insulin secretion and insulin sensitivity in relation to fasting and 2-hour plasma glucose (PG) levels and to assess the independent contributions of their impairments to non-diabetic hyperglycemia. A total of 2157 Japanese workers (mean age 52.6±7.3 years and mean BMI 23.9±3.2 kg/m²) underwent an oral glucose tolerance test (OGTT). Of these subjects, 1125 had normal glucose tolerance (NGT), 525 subjects had isolated impaired fasting glucose (IFG), 159 subjects had isolated impaired glucose tolerance (IGT), 263 subjects had combined IFG and IGT, and 85 subjects had newly diagnosed type 2 diabetes. Insulinogenic index and Matsuda insulin sensitivity index (ISI) were significantly attenuated in subjects with normal but slightly elevated fasting PG, or in subjects with normal but slightly elevated 2-hour PG. Whereas, InsAUC₁₂₀/GluAUC₁₂₀ was not significantly decreased in those subjects, and significant decrease of it was observed exclusively in subjects with abnormal fasting PG (≥ 106 mg/dL) or abnormal 2-hour PG (≥ 221 mg/dL). Using multiple regression analyses, both Matsuda ISI and insulinogenic index were independently correlated with PG concentrations in subjects with IFG and/or IGT, while Matsuda ISI alone was independently correlated with fasting PG concentrations in normoglycemic subjects. In conclusion, both insulinogenic index and Matsuda ISI were significantly attenuated in subjects with normal but slightly elevated PG. Lowering of Matsuda ISI was likely to be a strong contributor to ‘elevation of fasting PG within the normal range’ in this population.

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There are several reports that sera from Graves’ patients contain heterophilic antibody (Ab) to animal IgG such as human anti-mouse antibody (HAMA). We examined the binding of TSAb and TBAb with heterophilic Ab. The binding of animal IgG with patient’s IgG was examined by the inhibition of animal IgG on the binding of labeled bovine (b) IgG with patient’s IgG. The binding to labeled bIgG was detected in the serum of 5 patients (2.7 %) among 185 patients with Graves’ disease. The binding of the labeled bIgG with patient’s IgG was inhibited by animal serum or the crude IgG (45% ammonium sulfate fraction of serum)(such as dog, horse, bovine, porcine, goat, ovine, rabbit, guinea-pig, rat, mouse) except human, monkey and chick. This heterophilic Ab which had cross-reaction with mammalian IgG (except human, monkey) was used as human anti-animal IgG Ab. TBII and TSAb activity of TSAb-positive serum, and TBII activity of TBAb-positive serum were neutralized by incubation with this Ab-bound column. Partial purification of TSAb- or TBAb- IgG from Protein A-purified TSAb- or TBAb-IgG was possible using this Ab-bound column. TBII and TSAb activity of TSAb-IgG and TBII activity of TBAb-IgG were neutralized by incubation with rabbit anti-human (h) IgG Ab (having cross-reaction with animal IgG). Further purification of Protein A-purified TSAb-IgG or TBAb-IgG by rabbit anti-hIgG Ab-bound column was impossible. The binding of TSAb and TBAb with heterophlic Ab means that TSAb-and TBAb-specific IgG have immunological similarity with mammalian species IgG compared to human IgG.

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Previously we reported neutralization and partial purification of TSAb and TBAb activity using heterophilic antibody (Ab) to animal IgG from Graves’ disease. Thus, we examined immunological similarity of TSAb and TBAb with animal IgG using experimentally generated anti-animal IgG [dog (d), bovine (b), porcine (p) and rabbit (rb)] Abs. TBII activity of TSAb- and TBAb-positive serum was neutralized by these anti-animal IgG Abs. Applied TSAb- or TBAb-IgG protein (purified by Protein A) on these anti-animal IgG Abs-bound column was found mainly in the unbound fraction (UF)(>65%) and partially in the bound fraction(BF)(<35%). The TBII and TSAb activity of TSAb-IgG in the BF showed significantly higher than the UF. Thus, the ratio of TBII activity (U/L)/mg protein in the BF/UF was high. TBII activity of TBAb-IgG was similarly purified by this column. We examined immunological characteristics of TSAb-and TBAb-Fab or F(ab’)₂ using rabbit anti-bF(ab’)₂ Ab. TBII and TSAb activity of TSAb-Fab or- F(ab’)₂ and TBII activity of TBAb-Fab or -F(ab’)₂ were neutralized by anti-bF(ab’)₂ Ab. Partial purification of TSAb- or TBAb-Fab and -F(ab’)₂ by anti-bF(ab’)₂ Ab-bound column was also possible. Immunological similarity of TSAb- and TBAb-IgG with animal IgG such as d, b, p, rb by anti-animal IgG Ab, and TSAb- or TBAb-Fab and -F(ab’)₂ with bFab by anti-bF(ab’)₂ Ab were demonstrated. These fact suggest that both Fab and Fc portion of TSAb- and TBAb-IgG molecule have immunological similarity with animal IgG.

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In this rodent study, we compared the effects of early versus late intensive insulin therapy on diabetic nephropathy and potential causal mechanisms. Diabetes was induced in rats by high-fat diet and low-dose streptozotocin. Intensive insulin therapy was initiated in the early intensive insulin therapy groups as soon as diabetes was confirmed and lasted for 8 (8wEI group) and 16 weeks (16wEI group). In the late insulin therapy group (LI group), intensive insulin treatment was initiated 8 weeks later and lasted for 8 weeks. Age-matched diabetic rats (8wDM group and 16wDM group) and non-diabetic rats (8wNC group and 16wNC group) served as controls. Histological analysis, real-time PCR, and western blot were performed in renal cortex specimens. Glomerular hypertrophy and mesangial matrix expansion were prominent in the 16wDM and LI groups while the EI groups remained normal and similar to the 16wNC group. Western blots revealed that p38 MAPK activities in the EI groups decreased significantly, whereas the level in the LI group was markedly higher than the 16wEI group, and not different from the DM groups. Activities of MKK3/6, CREB and MKP-1 proteins as well as CREB and MKP-1 mRNA showed a similar pattern. Therefore, we concluded that early intensive insulin treatment and attainment of good glycemic control counteracted some renal molecular pathways associated with epigenetic metabolic memory to minimize risk of diabetic nephropathy. However, late insulin therapy did not abrogate the increased renal cortical p38 MAPK pathway activation in diabetic rats and led to glomerular hypertrophy and extracellular matrix expansion.

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