Behavior is shaped by a variety of genetic and epigenetic mechanisms, including those underlying anxiety and fear. Neuropeptides are ideal candidates to be involved in the regulation of emotional facets as they are released within the brain and act as neuromodulators/neurotransmitters; furthermore, their large number is prone to direct changes by mutations. A variety of approaches have been used to reveal the physiological involvement of neuropeptides in anxiety-related behavior, including those focused on behavioral effects of neuropeptides and, vice versa, the influence of behavioral phenomena on intracerebral neuropeptides. In concert with other neuropeptides and classical transmitters, particularly CRH and vasopressin are promising candidate neuropeptides to determine not only the activity of the hypothalamo-pituitary-adrenocortical axis, but also anxiety-related behavior including its cognitive components. CRH and vasopressin interactions with specific receptor subtypes have been shown to induce consequences on emotionality, and CRH and vasopressin responses to both anxiogenic stimuli and extreme levels of inborn anxiety confirm their critical involvement in normal and pathological anxiety. Based on behavioral and neuroendocrine data obtained from proper animal models, the neurobiological and genetic analyses of anxiety and fear will provide the prerequisites to develop novel and more causal therapeutic strategies for anxiety disorders.

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Alterations in thyroid hormone regulation and metabolism, such as low serum T3 and T4 with normal TSH, are frequently noted in liver cirrhosis, but few morphological studies have ever been done on thyroid tissue in liver cirrhosis. In this study we analyzed the histological changes of thyroid tissue in the patients with liver cirrhosis. Specimens of thyroid gland obtained from autopsies in 16 cirrhotic patients were examined, and compared with those of two control groups. Control group I consisted of 7 patients with diabetes mellitus and control group II, 12 patients who died from sudden onset of cardiovascular problems. We measured follicular diameter and epithelial width on light micrographs of the central portion of thyroid specimens. We graded the degree of colloid vacuole, lipofuscin deposition in follicular epithelia, regenerative reaction and perivascular fibrosis in 10 consecutive light microscopic fields of the specimen. In the cirrhotic group, mean follicular diameter and epithelial width were significantly shorter and thinner, respectively, than those in the two control groups. Perivascular fibrosis was more prominent in the cirrhosis group than in the controls. These findings suggest that thyroid glands in patients with liver cirrhosis have the characteristic features of hypoactivity.

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The purpose of this study was to investigate the TaqI vitamin D receptor (VDR) polymorphism in both Japanese prostate cancer patients and Japanese noncancer controls in order to determine if an association exists between VDR genotype with clinical and pathological risk of prostate cancer patients. This study involved 115 patients with prostate cancer and 133 male age-matched noncancer controls genotyped for a previously described TaqI restriction fragment length polymorphism (RFLP) at codon 352 in exon 9 of the VDR gene. Products were digested into T allele or t allele according to the absence or presence of TaqI restriction site with individuals being classified as TT, Tt, or tt. The genotype tt was higher among the control group (6.0%) compared to the patients with prostate cancer (1.8%), but not so (OR=0.28; 95% CI, 0.06-1.33; p=0.081). In addition, the genotype TT was statistically higher among patients with locally advanced or metastatic disease (T3/T4/N1/M1) compared to controls (OR=2.52; 95% CI, 1.21-5.27; p=0.009). Lastly, the genotype TT was statistically higher among patients with poorly differentiated adenocarcinoma compared to controls (OR=5.38; 95% CI, 1.57-18.50; p=0.002). These data demonstrate that VDR genotype plays an important role in determining the risk of more clinically advanced and pathologically aggressive prostate cancer which is associated with a higher mortality rate in Japanese men.

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The effect of voluntary wheel-running on insulin resistance was studied in high-fat-fed rats. A sequential hyperinsulinemic euglycemic clamp procedure was employed (insulin infusion rates: 3 and 30mU/kg BW/min) in 14 high-fat-fed rats and 7 chow-fed rats under the awake condition. The high-fat-fed rats were further divided into a sedentary (n=7) and a voluntary wheel-running (n=7) groups. Blood glucose was clamped at the fasting level in each rat. Plasma insulin levels during the 3- and 30-mU/kg BW/min insulin infusions were 40-50 and 450-550μU/ml, respectively. At both 3 and 30mU/kg BW/min insulin infusions, high-fat-feeding showed a significant decrease in glucose infusion rate (GIR), compared with the chow-fed rats. However, decreased GIRs were restored by the 4-wk wheel-running and reached similar levels as the chow-fed rats. Therefore, it could be concluded that voluntary wheel-running prevents insulin resistance induced by high-fat feeding.

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Ovarian 20α-hydroxysteroid dehydrogenase (20α-HSD), which converts progesterone to a derivative devoid of biological activity, plays a crucial role in achieving the short estrous cycle in rats. Although 20α-HSD activity has also been demonstrated in the thymus, its molecular nature, function, and regulation of expression have yet to be determined. In the present study we investigated if 20α-HSD activity in the thymus originates in a transcript identical to that expressed in the ovary. RT-PCR analysis indicated the expression of 20α-HSD mRNA in rat thymus, and sequencing of the PCR product showed 100% identity to ovarian 20α-HSD cDNA. Immunohistochemical study using anti-rat ovarian 20α-HSD antibody demonstrated the expression of 20α-HSD protein in the thymus. The 20α-HSD-expressing cells in the thymus seemed to be some type of lymphocyte by their morphology. These results suggest that the same molecular species as ovarian 20α-HSD is expressed in thymic lymphocytes. Therefore, 20α- HSD may play a role in T-lymphocyte proliferation and differentiation processes.

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Two cases of hypothyroidism with cardiac attack (acute myocardial infarction, AMI) following thyroxine replacement were reported. Neither of these cases showed any major coronary artery disease. The first case was a 58 year-old male who was treated with L-thyroxine (initial dose 0.025mg/day) for hypothyroidism due to Hashimoto's disease. The dose was increased up to 0.1mg/day within 2 weeks. Acute myocardial infarction occurred 6 weeks after the replacement was started. Angiographical study showed no notable pathological change in major coronary arteries, but echocardiography demonstrated diffuse hypokinesis of the left ventricular wall. The second case was a 61-year-old female who suffered from Graves' disease and had been treated with thiamazole (2.5mg/day) for 15 years. Later, she became hypothyroid and was treated with thyroxine. At first, 0.05mg/day of L-thyroxine was given, and then the dose was increased up to 0.1mg/day after the 7^th week. Acute myocardial infarction occurred 3 weeks after the dose was increased. Angiographic study of the coronary arteries revealed no abnormality. Possible causes of AMI in thyroxine replacement were discussed in relation to vascular spasm and small vessel disease of the heart. Importance of echocardiographic study before hormone replacement therapy is stressed, particularly for middle/old-aged patients with long-term hypothyroidism.

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Pretreatment serum level of testosterone (T) is a potential prognostic factor for prostate cancer. However, T levels in Japanese prostate cancer patients are unknown to date. To evaluate the clinical significance of pretreatment serum T level in such patients, serum T level was analyzed in relation to several clinical factors in a total of 130 patients with various stages of prostate cancer, 74 of whom had metastatic disease (stage D2) and received endocrine therapy as first-line treatment. The mean pretreatment T level in patients with non-metastatic prostate cancer (stages B+C) was significantly lower than that in stage D2 patients (B+C: 4.05±2.01ng/ml; D2: 4.85 ±2.18ng/ml, p=0.0344). On the other hand, the mean serum level of T was higher in stage D2 patients who showed good response to endocrine therapy (CR: 5.42±1.55ng/ml; non-CR: 4.30±2.63ng/ml, p=0.0320). When the 74 stage D2 patients were divided into high and low T level groups according to the median value, those patients with a high T level had significantly better cause-specific and progression-free survival. Multivariate analysis demonstrated that extent of bone metastases (EOD) grade, pretreatment serum T level and tumor marker response to endocrine therapy were significant predictors for progression-free survival. In conclusion, a higher pretreatment T level appears to be predictive of the marker response to endocrine therapy, showing positive prognostic value and indicating good prognosis in patients at the metastatic stage. However, a higher T level was also associated with stage progression of this disease.

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Growth hormone-deficient hypopituitary patients on conventional replacement therapy have increased mortality and morbidity from atherosclerotic cardiovascular disease. Oxidation of low-density lipoprotein (LDL) is a key event in the development and progression of atherosclerosis. Antibodies against oxidatively modified LDL may reflect in vivo oxidation processes. The aim of this study is to determine the effect of growth hormone deficiency on oxidised-LDL antibody titres in panhypopituitary patients taking conventional replacement therapy. Twenty-one GH deficient, adult panhypopituitary patients and 17 age, sex and body mass index-matched healthy controls were studied. After an overnight fast, anthropometric parameters were measured and body composition was determined by a bioelectrical impedance analyser. Venous blood samples were obtained for the measurements of biochemical parameters. Antibodies to oxidised-LDL were analysed by an ELISA system in the patients' and controls' serum. No significant difference was observed between the oxidised-LDL antibody titres in hypopituitary patients and controls (395.4±183.2mU/ml and 393.2±186.2mU/ml respectively, p=NS). A significant positive correlation was observed between oxidised-LDL antibody titres and total cholesterol concentrations in the patients (r=0.449, p<0.05). No significant correlation was observed between oxidised-LDL antibody titres and anthropometric/biochemical variables in the controls. It is concluded that relatively increased LDL oxidation may not contribute to the progression of atherosclerosis in hypopituitary patients.

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Sheehan's syndrome and lymphocytic hypophysitis often occur in relation to pregnancy, making their differentiation difficult. We describe a 52-yr-old woman with hypopituitarism, Hashimoto's thyroiditis and candidiasis. She was admitted to our hospital because of nausea, vomiting and constipation. Her menstruation stopped in her early thirties. She thereafter developed kyphosis and loss of axillary and pubic hair. Levels of serum Na, Cl and glucose were all low, and hormonal studies were consistent with anterior pituitary hypofunction. Although she had blood transfusion because of hemorrhage at her first delivery, the delivery of her second child was normal followed by resumption of regular menstruation. In addition to hypopituitarism, she had Hashimoto's thyroiditis and candidiasis. Laboratory tests showed an increased Th1 ratio, which is related to induction of cellular immunity, and the presence of HLA DR4, which is often associated with polyglandular autoimmune syndrome. These results suggested that the pituitary lesion might be due to lymphocytic hypophysitis rather than Sheehan's syndrome.

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We evaluated the incidence of childhood thyroid diseases and urinary iodine levels in Nagasaki, Japan and in Gomel, Belarus, which was greatly radio-contaminated by the Chernobyl accident, in order to obtain the comparative data of thyroid diseases between iodine-rich (Japan) and -deficient (Belarus) areas. In Nagasaki, the median level of urinary iodine, measured by ammonium persulfate digestion in microplate method, was 362.9μg/L. In order to evaluate the geographical differences in Japan, other samples were collected in Hamamatsu and in South Kayabe, Hokkaido, where the median levels were 208.4μg/L and 1015.5μg/L, respectively. Furthermore, thyroid screening by ultrasound (US) in Nagasaki revealed only four cases that showed goiter (1.6%) and two cases (0.8%) that had cystic degeneration and single thyroid cyst. There was no evidence of thyroid nodule detected by US examination. In contrast, the median of urinary iodine level was 41.3μg/L in Gomel. The incidences of goiter (13.6%) and echogenic abnormality (1.74%) in Gomel were much higher than in Nagasaki, suggesting the critical involvement of iodine deficiency in increased childhood thyroid abnormality around Chernobyl. Radioactive iodine released just after the Chernobyl accident may have influenced predominantly children residing in iodine-deficient areas. Our results suggest that management of thyroid screening for schoolchildren at ordinary times may be beneficial for monitoring the adverse effects of radioactive iodine from the standpoint of future prospective study.

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Expression of extra pituitary prolactin (PRL) has been recently reported in the mammary gland. However, spontaneous mammary tumors occurring in aging rats have not been investigated for PRL production. The present study was undertaken to examine the expression of PRL gene in rat mammary tumors spontaneously arisen in rats with pituitary prolactinomas among 130 female Fischer-344 (F-344) rats. The tumors examined were fibroadenoma (adenomatous type) in the 18-month old rat and adenocarcinoma (alveolar/tubular type) in the 21-month old rat. PRL mRNA was examined by solution and in situ reverse transcription-polymerase chain reaction (RT-PCR) method. The predicted amplified products for PRL mRNA were identified in both tumors, and its expression was confirmed to be in the cytoplasm of epithelial cells. The results of the present study showed that PRL gene is expressed in spontaneously arising mammary tumors.

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