Bone morphogenetic proteins (BMPs) were originally identified with regard to their actions to regulate ectopic formation of bone and cartilage and early embryonic development. Subsequently, our research program has investigated a BMP system that exists in the mammalian ovary and plays roles in regulating numerous granulosa cell functions. BMP ligands including BMP-2, -4, -6, -7 and -15 were found to inhibit gondotropin-dependent progesterone synthesis by granulosa cells, which led to the hypothesis that BMPs are a physiological luteinization inhibitor in growing ovarian follicles during the follicular phase of the ovarian cycle. The physiological importance of the BMP system for normal mammalian reproduction has been further recognized by the discovery of aberrant reproductive phenotypes of female sheep and humans having mutated genes encoding BMP-15. Physiological roles of BMPs in the pituitary, hypothalamus, adrenal and other tissues have also been discovered. Here we discuss recent advances in the understanding of autocrine/paracrine actions of BMPs in the systemic regulation of endocrine function.

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Progression to overt hypothyroidism and the associated adverse effects on lipid metabolism and the cardiovascular system are major concerns for patients diagnosed with subclinical hypothyroidism (SCH). No consensus regarding the clinical parameters associated with prognosis for this mild thyroid dysfunction has yet been established, although elevation of serum anti-thyroid peroxidase antibody (TPOAb) and decreased or heterogeneous echogenicity (diffuse thyroid disease, DT) on ultrasonography (US) are commonly observed. We investigated the value of ultrasonographic examination compared to the measurement of serum TPOAb and anti-thyroglobulin antibody (TgAb) for the evaluation of levothyroxine treatment on SCH. We analyzed 204 SCH patients who initially underwent thyroid ultrasonography and were given a low dose of levothyroxine for a mean of 6.94 months. Outcome was determined by the normalization or sustained elevation of serum TSH, and evaluated according to the presence of DT on subsequent US and serum TPOAb or TgAb. Sustained TSH elevation after levothyroxine replacement was more frequent in patients who initially showed DT on US, regardless of thyroid autoantibody level. Ultrasonographic morphology had a higher negative predictive value (81.8%) compared with the absence of TPOAb (73.9%) or TgAb (73.7%) and a similar positive predictive value (48.9%) to that of thyroid autoantibodies (46.8% for TPOAb and 50.0% for TgAb) in the outcome prediction of SCH. Thyroid US may provide valuable information on the course of SCH, and DT pattern can serve as a prognostic factor when combined with other known parameters.

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Subclinical hypothyroidism (SCH) is thought to have an influence on stroke outcomes. However, few reports demonstrate a favorable relationship between the two. We evaluated this association in acute ischemic stroke. From Jan 2005 to Jun 2008, 756 acute ischemic stroke patients were recruited within seven days of onset. The patients with overt hypothyroidism/hyperthyroidism or other medical conditions that may affect thyroid function were excluded. Thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were measured within two days. Patients were divided into two groups: the SCH group (TSH > 5.0 μU/mL and normal FT4 levels) and the control group. Stroke outcomes were assessed using two different criteria. In the first outcome model, favorable outcomes [I] were simply defined by modified Rankin Scale (mRS) scores (≤ 1), while the favorable outcomes [II] were defined as follows: a) a mRS score of 0, if the baseline National Institute of Health Stroke Scale (NIHSS) scores were < 8, b) a mRS score of 0 or 1, if the NIHSS scores were 8-14, c) a mRS score 0-2, if the NIHSS scores were >14. The changes in mRS scores and the proportion of patients with favorable outcomes [I] or [II] at the 30^th and 90^th day were compared between the two patient groups. Of the 756 patients, 31 (4.1%) were patients with SCH. More patients from the SCH group showed improvement in NIHSS scores on the 30^th day compared to the control group (48.4% vs. 25.3%, p=.006). In addition, the proportion of patients who exhibited favorable outcomes [I] was significantly higher in the SCH group on the 90^th day (74.2% vs. 55.3%, p=.027) and that trend was seen as early as the 30^th day (p=.102). Similarly, the proportion of the patients with favorable outcomes [II] was significantly greater in the SCH group both on the 30^th (29.0% vs. 14.6%, p=.039) and 90^th day (58.0% vs. 31.0%, p=.003). We found that acute ischemic stroke patients with SCH at admission were more likely to show favorable functional outcomes than those without SCH. We can suggest preconditioning before the stroke combined with a reduced response to stress as a possible protective mechanism.

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Small-cell carcinoma (SCC) of neuroendocrine type is an uncommon tumor of the endometrium. No previous report has documented Cushing’s syndrome due to ectopic ACTH production by SCC of the endometrium. We describe a 56-year-old Japanese woman with SCC of the endometrium and multiple lung metastases presenting as Cushing’s syndrome. The patient was referred to our hospital because of general fatigue with facial and leg edema, and multiple nodular lesions in the bilateral lungs on chest X-ray examination. A physical examination revealed that the patient had moon face, buffalo hump, and truncal obesity. Endocrinological examinations confirmed ACTH-dependent Cushing’s syndrome. Thoracic computed tomography imaging showed multiple nodular lesions in the bilateral lungs. Abdominal magnetic resonance imaging suggested a malignant tumor of the uterus. The patient received a lung tumor biopsy and surgical hysterectomy. The endometrial carcinoma was histologically a SCC admixed with endometrioid adenocarcinoma. The SCC of the endometrium showed immunoreactivity for pro-opiomelanocortin, ACTH, and vimentin, but not for thyroid transcription factor-1. The lung biopsy specimen had the same features. These findings indicated that the SCC originated from the endometrium, and the ectopic ACTH-producing tumor caused Cushing’s syndrome. This study provides the evidence that SCC of endometrial origin was an ectopic ACTH-producing tumor causing Cushing’s syndrome.

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High-fat diets induce an expansion of the adipose tissue (AT) that can be characterized by chronic low-grade inflammation. AT is an important source of adipokines and pro-inflammatory cytokines. The purpose of this study was to evaluate the effects of a shift from a high-fat diet to high-carbohydrate (CHO) diet on the blood levels of adipokines and pro-inflammation cytokines in mice fed a high-fat diet. Six-week-old male C57BL/6 mice were fed a high-fat diet (40% of the total calories) for 9 weeks to induce obesity, and then the diet was shifted to a high CHO diet (70% of the total calories) for 3 weeks. Body weight and organ weight as well as blood lipid levels were measured. The serum levels of adipokines and pro-inflammatory cytokines were analyzed. Shifting the diet from high fat to high CHO decreased significantly body weight, adipose tissues, and liver weight (p < 0.05). The lipid blood levels (TG, Total-chol, and LDL-chol) decreased. The leptin and resistin blood levels significantly decreased after the diet was shifted to a high-CHO diet (p < 0.05); however, the adiponectin concentrations did not change. The IL-6 levels were also significantly decreased by the high-CHO diet (p < 0.05). The IL-13 serum levels were significantly increased by the high-CHO diet (p < 0.05). Further, the serum levels of the TNF-α and supernatant IL-1β concentrations in mice fed a high-carbohydrate diet were significantly increased after the mice were shifted to a high-fat diet. On the other hand, the serum IL-4 and supernatant levels did not change. Conclusively, reduction of body weight and adipose tissues through shifts from a high-fat diet to a high-carbohydrate diet effectively improved low-grade inflammation states in mice fed a high-fat diet. Particularly, the reduction of body weight was associated with the levels of leptin, resistin, and IL-6.

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There is growing evidence of a link between lipid and bone metabolism, although data on this association in European men are scarce. This cross-sectional study from a community-based prospective cohort aims to explore the association of serum lipids with different aspects of bone metabolism in Spanish men. Demographic and anthropometric measurements, biochemical parameters including serum lipids, bone remodelling markers and calciotropic hormones, bone mineral density (BMD) assessed by dual X-ray absorptiometry and heel quantitative ultrasound, and prevalent vertebral and non-vertebral fractures, were evaluated in 289 men. Calciotropic hormones or bone markers were not associated with serum lipids. Serum total (TC) and LDL cholesterol, as well as LDL/HDL ratio were positively correlated to BMD at lumbar spine and hip. No significant correlation was noted for triglycerides or HDL. We observed a positive association between triglycerides, LDL/HDL ratio and BUA, and between TC/HDL ratio and both, QUI and BUA. BMD at the femoral neck and total hip was significantly higher in men with hypercholesterolemia after controlling for all the covariates (p=0.007). We did not observe any association between serum lipids and prevalent vertebral fractures. However, we found that TC (p=0.03) and LDL (p=0.04) were lower in subjects with non-vertebral fractures. In conclusion, we have found that a more unfavorable lipid profile (mainly higher LDL-C levels) is associated with higher BMD at lumbar spine and hip in Spanish men. Moreover, we did not observe any association between hypercholesterolemia and prevalent vertebral fractures, but we found lower serum TC and LDL-C levels in men with prevalent non-vertebral fractures.

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Monocytes/macrophages are key mediators of wound repair, tissue remodeling, and inflammation. However, the molecular mechanisms underlying macrophage recruitment to the site of inflammation is not fully understood. Leptin acts directly on the hypothalamus, thereby regulating food intake and energy expenditure. The leptin receptor, a single transmembrane protein that belongs to the gp130 family of cytokine receptor superfamily, is expressed not only in the hypothalamus but in a variety of peripheral tissues, suggesting the role of leptin as a pro-inflammatory adipocytokine in peripheral tissues. Here, we show that deficiency of leptin signaling reduces renal macrophage infiltration after unilateral ureteral obstruction (UUO). Bone marrow transplantation studies using leptin signaling-deficient db/db mice revealed that leptin signaling in bone marrow cells may not play a major role in the UUO-induced renal macrophage infiltration. Interestingly, central leptin administration reverses the otherwise reduced UUO-induced renal macrophage infiltration in leptindeficient ob/ob mice. This is effectively abolished by central co-administration of SHU9119, a melanocortin-3 receptor/melanocortin-4 receptor antagonist. This study demonstrates that central leptin administration in ob/ ob mice accelerates renal macrophage infiltration through the melanocortin system, thereby suggesting that the central nervous system, which is inherent to integrate information from throughout the organism, is able to control peripheral inflammation.

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Propylthiouracil (PTU) is known to induce myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) in patients with Graves disease (GD). Previously, we showed that serum MPO-ANCA were frequently seen in patients with GD treated with PTU. In this study, we analyzed 13 patients with positive MPO-ANCA examining a long-term clinical consequence of these patients as well as antibody titers during 5.6 ± 3.0 years. PTU therapy was continued in 8 patients and discontinued in 5 patients. Antibody titers decreased in 7 of 8 patients who discontinued PTU therapy but remained positive in 5 patients 5 years after PTU withdrawal. The initial MPO-ANCA levels were significantly higher in those antibody titers remained positive for longer than 5 years (n=5) than in those titers turned to be negative within 5 years after PTU withdrawal (n=3) (203 ± 256 EU and 22 ± 2 EU, respectively, P=0.04), but there were no significant differences in age, gender, duration of PTU therapy or dosage of PTU. Among 5 patients who continued PTU therapy, 2 patients with initially low MPO-ANCA titers turned to having negative antibody. No patients had new symptoms or signs of vasculitis throughout the follow-up periods. The long-term follow-up study suggests that higher MPO-ANCA levels remain positive for years after PTU withdrawal but are rarely associated with vasculitis.

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The purpose of these studies was to explore the expression pattern of miRNAs associated with invasion and metastasis of human papillary thyroid carcinoma (PTC). A transwell invasion chamber was used to select progressively more invasive cancer cell populations from a clonal cell line of human PTC with cervical lymph node metastasis, IHH-4. Three sublines with progressive invasiveness, designated IHH-4M-1, IHH-4M-2 and IHH-4M-3, were obtained through this in vitro selection process. The sublines manifested an increase in colony-forming ability on soft agar and metastatic potency in nude mice. Then metastasis-related miRNAs differentially expressed between them were analyzed utilizing the miRNA microarray technique. We found that 11 metastasis-related miRNAs were differentially expressed between the invasive subpopulations and their control subpopulations; these miRNAs may account for their significant difference in the invasion capabilities and favor lymphatic metastasis of PTC.

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We screened urinary iodine (UI) concentrations in high background radiation areas of the Kanyakumari district of Tamilnadu, India. We collected 331 urine samples from three villages in the district: Chinna-Villai, Kadiyapatinam, and Pallam-Annai nagar. The median UI concentrations were 257, 262, and 454 μg/L in Chinna-Villai, Kadiyapatinam, and Pallam-Annai nagar, respectively. Only 27 samples showed mild or moderate iodine deficiency (<100 μg/L) and none showed severe deficiency (<20 μg/L). These findings indicate that iodine supplementation in the villages is sufficient, probably as a result of appropriate fortification of iodized salt in the region. Further screening, including morphological and functional analysis of the thyroid gland, will be needed to clarify the health effects of chronic low-dose radiation exposure attributable to residing in a high background radiation area.

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We investigated the possible roles of estrogen on plasma membrane Ca²⁺-ATPase (PMCA) in human fibroblast-like synovial cells (HFLS) and mouse macrophage-like cells (RAW 264.7). Western blots revealed the expression of PMCA 2 and 4 in both cells. In vitro treatments with 17β-estradiol for 24 hours resulted in a concentration dependent decrease in PMCA expression. Moreover, Ca²⁺-ATPase specific activity was similarly decreased with estrogen treatments. However, treatments for 1 hour in the presence or absence of cycloheximide demonstrated non-significant effects. These results suggest that estrogen has a modulatory role on Ca²⁺ homeostasis through decreasing PMCA expression and abating their activity.

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