[A Case of SIADH in an Elderly Patient with Advanced Gastric Cancer].

An 82-year-old woman underwent surgery for gastric cancer at another hospital in May 2007. The pathological diagnosis was pT4a, pN2, M1, CY1, pStage Ⅳ. Although postoperative chemotherapy was administered, recurrence was observed on the abdominal wall in March 2014, and she was treated usingchemotherapy and resection. Intestinal obstruction due to peritoneal metastasis occurred in December 2017 and mid-July 2018 but symptoms improved with conservative treatment. In late August 2018, she was unable to eat and was readmitted to the hospital. Serum Na level at admission was low at 120 mEq/L, and Na correction was performed. Hyponatremia did not improve, and the serum Na level continued to decrease to 115mEq/L on the 14th day of hospitalization. Plasma osmolality was 229mOsm/kg, urine osmolality was 323mOsm/kg, and urine sodium concentration was 56mEq/L. Diagnosis of SIADH was made according to diagnosis standards. Hyponatremia improved by fluid restriction and Na correction. Subsequently, her peritoneal metastasis exacerbated, and she died in mid- October. We would like to report a case of SIADH in an elderly patient with advanced gastric cancer.

[A Case of Rectal Cancer Presenting with Perianal Abscess].

An 81-year old man with a perirectal abscess was referred in May 2017 by another hospital. We observed swelling in the anal region at the 4 o'clock position and performed incisional drainage. Although this alleviated the pain and inflammation in the anal region, the irritation recurred in early June. The patient presented with bloody stools and a low-grade fever since late June. Pelvic magnetic resonance imaging(MRI)confirmed a solid tumor in the center of the lower rectum(Rb), outside of the anal fistula. We surmised this was rectal cancer. Colonoscopy revealed an ulcerative invasive(Grade 3)tumor extending more than halfway around the Rb; a biopsy confirmed a diagnosis of differentiated adenocarcinoma. Surgery was the preferred treatment option; however, as the patient also had the complication of anal fistula, there were concerns that the cancerous cells would contaminate the intraperitoneal area during surgery. We subsequently we decided to construct a colostomy and then start chemoradiotherapy. The patient began radiotherapy in the beginning of August, and received S-1 as a sensitizer. Contrast computed tomography(CT)and MRI at the completion of chemoradiotherapy confirmed that the rectal cancer had reduced in size. We scheduled later surgery, but the patient declined and preferred to continue with S-1. The tumor has continued to decrease in size, with good local control.

[A case of disseminated carcinomatosis of the bone marrow with disseminated intravascular coagulation caused by advanced colon cancer successfully treated with SOX/bevacizumab].

Our patient was a 58-year-old man who was diagnosed with a large bowel obstruction caused by ascending colon cancer, together with multiple liver metastases for which a right hemicolectomy was performed. After the operation, he developed disseminated intravascular coagulation(DIC)and severe anemia. Bone marrow biopsy findings led to a diagnosis of disseminated carcinomatosis of the bone marrow caused by colon cancer. We administered S-1+oxaliplatin(SOX) and bevacizumab( BV)chemotherapy, which improved the DIC. The patient was discharged from the hospital. After a total of six courses of chemotherapy, the carcinoma became resistant. We changed the drug regimen and his clinical condition improved. He survived for 292 days from the onset of disease.

ACTH response to desmopressin in a patient with acromegaly; expression of corticotropin-releasing factor, urocortins and vasopressin V1b receptor in GH-producing pituitary adenoma.

GH-producing pituitary adenomas frequently co-produce other certain anterior pituitary hormones, such as prolactin (PRL). In contrast, GH-producing adenomas which express all of corticotropin-releasing factor (CRF), urocorin1 (Ucn1) and urocortin3 (Ucn3) have not been reported. A 39-year-old woman was admitted for evaluation of the pituitary tumor. The diagnosis of acromegaly was confirmed by elevated serum GH and IGF-I levels, and the absence of GH suppression by oral glucose tolerance test. ACTH response to desmopressin (DDAVP) was observed (plasma ACTH levels increased from 13.9 to 50.4 pg/ml at 90 min). Although it is known that ACTH response to DDAVP is considerably useful for the diagnosis of ACTH-dependent Cushing's syndrome, the diagnosis of Cushing's disease was not supported by the criteria. The patient underwent transsphenoidal resection of the pituitary tumor. Immunohistological examination confirmed a GH- and PRL-producing adenoma, whereas ACTH was negative. ACTH response to DDAVP disappeared after tumor removal. To determine the cause of preoperative ACTH response to DDAVP, we examined expression of CRF family peptides and vasopressin V1b receptor in the pituitary adenoma by immunohistochemistry. Immunohistochemistry revealed positive immunostaining for CRF, Ucn1, Ucn3 and vasopressin V1b receptor in the adenoma. These observations raised the possibility that DDAVP caused an ACTH response, perhaps via the paracrine effects of tumor-derived CRF and Ucn1. When ACTH response to DDAVP is observed in patients with pituitary tumor, not only the direct effect of DDAVP on ACTH secretion, but also a possible involvement of CRF and/or urocortins expressed in the pituitary adenoma, should be considered.

Relationship between Willingness and Psychological Characteristics of Suicide Prevention Telephone Counselors: A Retrospective Observational Study.

Suicide is a major public health issue worldwide, and telephone counseling is an important preventive measure. As the number of telephone counselors is insufficient in Japan, public needs cannot be fully met. Willingness is important for securing telephone counselors, but few studies have examined the willingness to engage in telephone counseling activities. Therefore, we investigated the relationship between telephone counselors' willingness to perform their activities and their psychological characteristics, health status, and received social support. In this study, a questionnaire survey was conducted by mail among telephone counselors belonging to the Federation of Inochi No Denwa in Japan. The total number of valid responses was 709 (recovery rate: 50.4%). Following an exploratory factor analysis, three factors were extracted: (1) willingness to engage in telephone counseling activities, (2) sense of being burdened by telephone counseling activities, and (3) sense of difficulty in coping. Structural equation modeling, using all the factors, showed that social support and grit were directly related to the willingness to engage in telephone counseling activities, while physical health, mental health, and general self-efficacy were indirectly related to it. The findings obtained may be useful in devising concrete measures for telephone counselors to continue their activities.

Immunolocalization of urotensin II and its receptor in human adrenal tumors and attached non-neoplastic adrenal tissues.

Urotensin II (UII), first identified from goby urophysis, is a potent vasoactive peptide hormone and an endogenous ligand for an orphan G protein-coupled receptor GPR14, now named urotensin II receptor (UT-R). In addition to its vascular actions, UII has been shown to have mitogenic effects on tumor growth and some regulatory effects on adrenal steroidogenesis. In the present study, we examined expression of UII and UT-R in human adrenal tumors and attached non-neoplastic adrenal tissues by immunohistochemistry. Both UII and UT-R were immunolocalized in tumor cells of all adrenal tumors examined: 8 cases of cortisol-producing adenomas, 8 cases of aldosterone-producing adenomas, 2 cases of non-functioning adenomas, 17 cases of adrenocortical carcinomas, and 8 cases of pheochromocytomas. In attached adrenals, immunoreactivity for UII was detected in medulla, but much weaker in the cortex than in cortical tumors, suggesting that expression of UII was up-regulated in neoplastic adrenocortical tissues. No significant differences were found in the degree of immunoreactivity for UT-R between the tumors and the attached adrenal tissues. The present study showed that both UII and UT-R were expressed in the adrenal tumors and attached non-neoplastic adrenal tissues, and suggests possible roles of UII and UT-R in tumor growth and/or secretory activities of these tumors.

Expression of peptide YY in human brain and pituitary tissues.

Expression of peptide YY (PYY) in the human brain and pituitary tissues was studied by radioimmunoassay, immunocytochemistry, and reverse transcription polymerase chain reaction. The polyclonal antibody raised against human PYY(1-36) in a rabbit was used in the assay, which showed 100% cross-reactivity with PYY(3-36) and no significant cross-reactivity with other peptides including neuropeptide Y and pancreatic polypeptide. The highest concentration of immunoreactive PYY was found in the hypothalamus (0.44+/-0.060 pmol/g of wet weight, mean +/- SEM, n=8), followed by the pituitary (0.41+/-0.16 pmol/g of wet weight, n=3). Reverse-phase high performance liquid chromatography of tissue extracts of human rectum and cortical brain showed a peak eluted in the position of authentic PYY(1-36) and PYY(3-36). Immunocytochemistry showed positive immunostaining for PYY in neurons of the paraventricular, arcuate, and supraoptic nuclei of the human hypothalamus. Moreover, reverse transcription polymerase chain reaction analysis showed expression of mRNA for PYY in human brain and pituitary tissues. The present study has shown for the first time expression of PYY in the human brain and pituitary tissues, suggesting a role for PYY as a neurotransmitter, in the neuroendocrine physiology, such as regulation of appetite and energy expenditure and modulation of pituitary hormone secretion.

Immunohistochemistry of a proliferation marker Ki67/MIB1 in adrenocortical carcinomas: Ki67/MIB1 labeling index is a predictor for recurrence of adrenocortical carcinomas.

Adrenocortical carcinoma (ACC) is a rare, highly malignant tumor. The aim of the present study is to evaluate the prognostic relevance of a proliferation marker Ki67/MIB1 by immunohistochemistry in 17 cases who underwent resections of the primary tumors and diagnosed to have ACC at Tohoku University Hospital based on the criteria of Weiss during the period from 1976 to 2005. The follow-up periods ranged from 221 days to 10659 days (about 29 years) with the median of 1895 days. The median age at diagnosis was 46 years old, and the mean size of the primary tumors was 7.1 cm with the minimal of 3.5 cm. Ki67/MIB1 labeling index (Ki67/MIB1LI) ranged from 1% to 26%. Kaplan-Meier analysis revealed that patients with Ki67/MIB1LI of 7% or more were associated with significantly shortened disease-free survival (P = 0.0037). The evaluation with Weiss criteria revealed that the median score of Weiss criteria was five, and 13 patients (76.5%) presented positive findings in the criteria of mitotic rate. The survival analysis with Weiss score showed that patients with the scores of 6 or more had both significantly shortened disease-free survival (P = 0.0001) and overall survival (P = 0.0063). The present study has suggested that Ki67/MIB1LI, as well as Weiss score, is a useful predictor for tumor recurrence after resection of the primary tumors in patients with ACC.

Acromegaly with normal IGF-1 levels probably due to poorly controlled diabetes mellitus.

Acromegaly is characterized by the somatic disfigurement and excessive production of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Here we report a patient with aromegaly and diabetes mellitus, who showed normal IGF-1 levels in spite of elevated GH levels. The patient was a 52-year-old woman with acromegalic manifestations. Serum GH level was elevated (32.4 ng/mL) with hyperglycemia (fasting plasma glucose, 277 mg/dL) and an extremely high level of glycosylated hemoglobin (HbA1c 17.7%), whereas serum IGF-1 level was within normal range (110 ng/mL, normal range 37-266). Brain magnetic resonance imaging detected a pituitary tumor, with involvement of the right cavernous sinus. Oral glucose tolerance test (OGTT) showed no suppression of serum GH. Thyrotropin-releasing hormone test showed paradoxical increases in serum GH. We therefore diagnosed acromegaly accompanied with diabetes mellitus. A large amount of insulin (34 units/day) was required to control the blood glucose level. The patient was treated with octreotide, a somatostatin analogue, followed by transsphenoidal surgery. After the surgery, serum GH levels were suppressed by OGTT, although basal serum GH levels remained to be high. Basal serum GH levels, however, were normalized 5 months later. Blood glucose became well controlled by the diet alone. In contrast, serum IGF-1 increased to the range of 219-233 ng/mL. Pre-operative serum IGF-1 levels were low probably due to poorly controlled diabetes mellitus. In conclusion, the presence of normal serum IGF-1 levels cannot exclude the diagnosis of acromegaly especially when the patient is accompanied by diabetes mellitus.

Expression of adrenomedullin2/intermedin in human brain, heart, and kidney.

Adrenomedullin2/intermedin (AM2/IMD) is a novel member of the calcitonin/calcitonin gene-related peptide (CGRP) family. In the present study, we developed a specific radioimmunoassay of human AM2/IMD. Expression of AM2/IMD was studied in the human brain, pituitary, heart and kidney obtained at autopsy by radioimmunoassay and immunocytochemistry. Immunoreactive-AM2/IMD was detected by radioimmunoassay in human brains (range; 0.163-1.495 pmol/g wet weight), pituitaries (4.46+/-0.689 pmol/g wet weight, mean+/-S.E.M, n=3), left ventricles of hearts (0.251+/-0.0321 pmol/g wet weight, n=4), kidneys (3.49+/-1.18 pmol/g wet weight, n=5), and plasma obtained at healthy subjects (24.7+/-1.78 pmol/l, n=3). Reverse-phase high performance liquid chromatography showed that immunoreactive-AM2/IMD in human brain, kidney and plasma extracts were eluted in the position of authentic AM2/IMD. Additional peaks eluted earlier were found in the brain tissue and plasma. Immunocytochemistry showed that immunoreactive-AM2/IMD was localized in paraventricular and supraoptic nuclei of hypothalamus, anterior and posterior lobes of pituitary, cardiomyocytes, pericardial adipocytes, vascular endothelial cells of pericardial veins, and vascular smooth muscle cells of coronary arteries and renal arterioles as well as in renal tubular cells. The present study has shown expression of AM2/IMD in various types of cells in the central nervous system and the cardiovascular system, and suggested possible (patho)physiological roles of AM2/IMD in these systems.

Maternal approaches to pup ultrasonic vocalizations produced by a nanocrystalline silicon thermo-acoustic emitter.

When infant rodents are isolated from their mother and littermates, they cool rapidly and emit ultrasonic vocalizations (USVs). The effect of pup USVs on the mother has been investigated using models of pup USVs from ultrasonic speakers. We used a nanocrystalline silicon thermo-acoustic emitter (nc-Si emitter) to investigate mothers' responses to digitally reproduced pup USVs in mice. The nc-Si emitter could reproduce ultrasonic sounds more accurately than conventional emitters. We compared the sound properties of pup USVs and reproduced USVs. We then investigated maternal responses to hypothermic pups, which emit USVs, and anesthetized pups, which are silent, as well as maternal responses to pup USVs reproduced by the nc-Si emitter and a silent mode. The nc-Si emitter can reproduce pup USVs very accurately in terms of duration, frequency, and sound pressure level. Mothers approached reproduced digitally recorded pup USVs from the nc-Si emitter and their behavior was similar to their behavior toward hypothermic pups. In contrast, mothers did not approach other synthesized ultrasounds, such as double-duration USVs, double-silence domain ultrasounds nor double-ultrasonic domain ultrasounds, indicating that they approach the specific profiles of pup USVs. These results indicate that the nc-Si emitter can be useful to elucidate the role of ultrasonic acoustic communication in rodents.

Expression of endothelin-1 and adrenomedullin was not altered by leptin or resistin in bovine brain microvascular endothelial cells.

Hypertension frequently occurs in obese subjects. It has been reported that leptin and resistin induce endothelin-1 expression in vascular endothelial cells. Altered function of brain microvascular endothelial cells may be related to increased occurrences of stroke in hypertensive patients. In the present study, we therefore studied the effects of leptin and resistin on the expression of endothelin-1 and adrenomedullin in bovine brain microvascular endothelial cells. Northern blot analysis showed that leptin (10(-10)-10(-8) mol/l), resistin (10(-10)-10(-8) mol/l) or a combination of leptin and resistin (10(-8) mol/l for each) had no significant effects on the expression of endothelin-1 mRNA or adrenomedullin mRNA in cultured bovine brain microvascular endothelial cells. On the other hand, hypoxia induced, and tumor necrosis factor-alpha (10 ng/ml) decreased, the expression levels of endothelin-1 and adrenomedullin mRNAs, indicating that the bovine brain microvascular endothelial cells were able to respond to hypoxia and tumor necrosis factor-alpha. Consistent with the results of Northern blot analysis, immunoreactive endothelin and immunoreactive adrenomedullin concentrations in the medium were not significantly changed by the treatment with leptin, resistin, or a combination of leptin and resistin. The present study thus showed that neither leptin nor resistin affects the expression of endothelin-1 or adrenomedullin in bovine brain microvascular endothelial cells.

Expression of orexin-A and orexin receptors in the kidney and the presence of orexin-A-like immunoreactivity in human urine.

Orexin-A (hypocretin-1), a neuropeptide with stimulatory actions on arousal and appetite, was originally shown to be specifically expressed in the hypothalamus. We studied expression of orexin-A and orexin receptors in the kidney and the presence of orexin-A-like immunoreactivity in human urine. Immunocytochemistry showed that orexin-A-like immunoreactivity and two types of orexin receptors (types 1 and 2) were localized in the tubules of the human kidney obtained at autopsy. Orexin-A-like immunoreactivity was detected in human kidneys (21.3 +/- 6.2 fmol/g wet weight, mean +/- S.E.M., n = 4) and rat kidneys (16.2 +/- 1.6 fmol/g wet weight, n = 5) by radioimmunoassay, although the levels were much lower than the levels in the brain. Orexin-A-like immunoreactivity was present in the urine obtained from male healthy volunteers (67.8 +/- 4.5 pmol/l, n = 5). Reverse phase high-performance liquid chromatography showed that most of orexin-A-like immunoreactivity of the urine extract was eluted earlier than authentic orexin-A, suggesting that orexin-A-like immunoreactivity in urine was modified to hydrophilic forms. Reverse transcriptase polymerase chain reaction showed expression of orexin receptors 1 and 2 mRNAs in the human kidney. These findings suggest that orexin-A is produced by the renal tubular cells and secreted into urine. Orexin-A may act on the kidney in the autocrine or paracrine fashion, or via the urine (urocrine fashion).

Hypoxia increases endothelin-1 mRNA expression but not immunoreactive endothelin in the medium of T98G glioblastoma cells under cytokine treatment.

Endothelin-1 (ET-1) levels in the culture medium were considered to reflect the transcription of the ET-1 gene and the subsequent secretion of ET-1 from cultured cells. It has not been clarified how different ET-1 mRNA expression levels and immunoreactive (IR)-ET levels in the culture medium are in the cell culture system. We studied ET-1 mRNA expression levels and IR-ET levels in the medium of T98G glioblastoma cells treated with cytokines. T98G glioblastoma cells were cultured with cytokines (interferon-gamma 100 U/ml, tumor necrosis factor-alpha 20 ng/ml and interleukin-1beta 10 ng/ml) under normoxia or hypoxia (1% O(2)). Northern blot analysis showed that ET-1 mRNA expression levels were increased by tumor necrosis factor-alpha alone or a combination of tumor necrosis factor-alpha and interleukin-1beta, or three cytokines, and the increase was further enhanced under hypoxia. Particularly, relative expression levels of ET-1 mRNA were significantly higher under hypoxia than in normoxia in the treatment with a combination of three cytokines. IR-ET levels in the medium were increased by treatment with tumor necrosis factor-alpha, interleukin-1beta or a combination of tumor necrosis factor-alpha and interleukin-1beta, or three cytokines. In contrast to the mRNA expression levels, IR-ET levels in the medium of T98G cells treated with a combination of three cytokines were rather decreased under hypoxia compared with those in normoxia. These findings indicate that hypoxia induces ET-1 mRNA expression in the treatment of three cytokines, but IR-ET levels in the medium do not reflect this induction in T98G glioblastoma cells.

Immunocytochemical localization of adrenomedullin 2/intermedin-like immunoreactivity in human hypothalamus, heart and kidney.

Adrenomedullin 2/intermedin (AM2/IMD) is a novel member of the calcitonin/calcitonin gene-related peptide (CGRP) peptide family. AM2/IMD has a vasodilator action, and antidiuretic and antinatriuretic effects in mice. The aim of the present study is to clarify immunolocalization of AM2/IMD in human hypothalamus, heart and kidney obtained at autopsy. Immunocytochemistry showed AM2/IMD-immunoreactive cell bodies in the paraventricular and supraoptic nuclei of human hypothalamus. Both parvocellular and magnocellular cells in the paravetricular nucleus are immunostained with AM2/IMD. Immunostaining of serial sections showed co-localization of AM2/IMD-like immunoreactivity and vasopressin in the paraventricular nucleus. Myocardial cells of the heart and renal tubular cells were positively immunostained with AM2/IMD, whereas neither renal glomeruli nor vasculature in the heart and kidney were immunostained. Reverse-transcriptase polymerase chain reaction confirmed expression of AM2/IMD mRNA in the brain, pituitary, heart and kidney. The present study has shown the wide expression of AM2/IMD in human hypothalamus, heart and kidney, raising the possibility that this novel peptide may be related to the central and peripheral regulation of the circulation and water-electrolyte metabolism.

Expression of urocortin 3/stresscopin in human adrenal glands and adrenal tumors.

Urocortin 3 (Ucn 3)/stresscopin (SCP) is a novel peptide of the corticotropin-releasing factor (CRF) family and is a specific ligand for the CRF type 2 receptor. In the present study, we studied expression of Ucn3/SCP in the normal adrenal and adrenal tumors by radioimmunoassay and reverse transcriptase-polymerase chain reaction (RT-PCR). High concentrations of immunoreactive (IR)-Ucn3 were present in the normal portions of adrenal glands (4.2+/-0.51 pmol/g wet weight, mean+/-S.E.M., n = 14), and the levels were higher than those in the brain. IR-Ucn3 was also detected in the tumor tissues of aldosterone-secreting adenomas (6.2+/-0.6 pmol/g wet weight, n = 10), cortisol-secreting adenomas (5.0+/-1.2 pmol/g wet weight, n = 4), and pheochromocytomas (1.9+/-0.4 pmol/g wet weight, n = 7). Reverse phase high performance liquid chromatography showed that IR-Ucn3 in normal portions of adrenal glands and aldosterone-secreting adenomas was eluted mainly in the positions of Ucn3 and SCP with several minor peaks eluting earlier. The RT-PCR showed expression of Ucn3 mRNA in normal portions of adrenal gland (positive ratio; 4/4), aldosterone-secreting adenomas (3/4), cortisol-secreting adenomas (1/3) and pheochromocytomas (6/7). These findings indicate that Ucn3 is produced in normal adrenal and adrenal tumors (both adrenocortical tumors and pheochromocytomas), and suggest that Ucn3 acts as an autocrine or paracrine regulator in normal adrenal and adrenal tumors.

Effects of adipokines on expression of adrenomedullin and endothelin-1 in cultured vascular endothelial cells.

Obesity is a major risk factor for the development of hypertension. Adipokines may cause hypertension by acting both centrally and directly on the vascular vessels. We wished to clarify whether three adipokines, leptin, resistin and tumor necrosis factor-alpha, affect expression of adrenomedullin and endothelin-1 in vascular endothelial cells. Human umbilical vein endothelial cells were cultured for 24 h with leptin (1-10 nmol/l), resistin (1-10 nmol/l) or tumor necrosis factor-alpha (1-10 ng/ml). Expression of adrenomedullin and endothelin-1 was examined by radioimmunoassay and northern blot analysis. Immunoreactive-adrenomedullin in the medium and adrenomedullin mRNA expression levels were decreased by treatment of tumor necrosis factor-alpha time- and dose-dependently, whereas endothelin-1 secretion was not significantly changed by it. Leptin or resistin had no significant effects on expression of adrenomedullin or endothelin-1 in human umbilical vein endothelial cells. Under hypoxic conditions (1% O2), expression of both adrenomedullin and endothelin-1 was induced in these cells. Immunoreactive-adrenomedullin levels in the medium were decreased by treatment of tumor necrosis factor-alpha under hypoxia. Leptin or resistin had no significant effects on adrenomedullin or endothelin-1 expression also in hypoxia. These findings have raised the possibility that decreased expression of adrenomedullin by tumor necrosis factor-alpha may be related to the increased risk of hypertension and other cardiovascular diseases in obese subjects.

Expression of urocortin III/stresscopin in human heart and kidney.

Urocortin III (Ucn III)/stresscopin (SCP) is a novel peptide of the corticotropin-releasing factor (CRF) family and is a specific ligand for the CRF type 2 receptor. We wished to clarify whether Ucn III/SCP is expressed in the human heart and kidney. Immunoreactive Ucn III was detected by RIA in the human heart (0.74-1.15 pmol/g wet weight, mean +/- SEM; n = 4) and kidney (1.21 +/- 0.30 pmol/g wet weight), which were obtained at autopsy. These levels were comparable to the levels in pituitary (2.72 +/- 0.13 pmol/g wet weight; n = 3) and brain tissues ( approximately 1-2 pmol/g wet weight). Furthermore, immunoreactive Ucn III was present in human plasma (51.8 +/- 16.0 pmol/liter; n = 5) and urine (266 +/- 20 pmol/liter; n = 5) obtained from healthy subjects. Reverse-phase HPLC showed a broad peak of immunoreactive Ucn III eluting in the position of synthetic Ucn III in the heart, kidney, and hypothalamus. Material eluting in the position of SCP was also found in the HPLC analysis of these tissue extracts. Immunocytochemistry showed positive staining of Ucn III in the myocardium and the renal tubules, particularly distal tubules. RT-PCR showed expression of Ucn III mRNA in the brain, pituitary, heart, and kidney. The present study has shown expression of Ucn III/SCP in the human heart and kidney as well as brain and pituitary tissues and its presence in plasma and urine. Ucn III/SCP may therefore regulate the cardiac and renal function as a local factor and a circulating hormone.

Nur-related factor 1 and nerve growth factor-induced clone B in human adrenal cortex and its disorders.

Nerve growth factor-induced clone B (NGFI-B; NR4A1) and Nur-related factor 1 (Nurr1; NR4A2) are members of NGFI-B family of orphan receptors. We recently demonstrated induction of CYP11B2 (aldosterone synthase) by Nurr1 and NGFI-B, suggesting possible important roles of these transcriptional factors in the regulation of adrenocortical steroidogenesis. Therefore, we immunolocalized Nurr1 and NGFI-B in various human adrenal specimens to study their biological significance. In nonpathological adrenal glands (n = 25), Nurr1 and NGFI-B immunoreactivities were detected at high levels in the fetal definitive zone or postnatal zona glomerulosa. NGFI-B immunoreactivity was increased according to development in the zona fasciculata, reaching a level similar to that in the zona glomerulosa in adult adrenal cortex. In adrenocortical neoplasms (n = 44), Nurr1 immunoreactivity was higher in aldosteronoma than in Cushing's adenoma or adrenocortical carcinoma. NGFI-B immunoreactivity was also higher in aldosteronoma than in adrenocortical carcinoma, but was not significantly different among the types of adenoma. Both Nurr1 and NGFI-B mRNA expressions were correlated with their immunoreactivities in adrenocortical neoplasms (n = 23), and mRNA expression of Nurr1 was significantly (P < 0.0001) associated with that of CYP11B2. These results suggest that the expression of Nurr1 and NGFI-B plays an important role in human adrenal cortex and its neoplasms, including possible regulation of steroidogenesis.

Urocortins as cardiovascular peptides.

Urocortins (Ucn) 1, 2 and 3, human homologues of fish urotensin I, form the corticotropin-releasing factor (CRF) family, together with CRF, urotensin I and sauvagine. Ucn 3 is a novel member of this family and is a specific ligand for CRF type 2 receptor. CRF type 2 receptor is thought to mediate the stress-coping responses, such as anxiolysis, anorexia, vasodilatation, a positive inotropic action on myocardium and dearousal. Endogenous ligands for the CRF type 2 receptor expressed in the cardiovascular tissues, such as the myocardium, have long been unknown. We have shown expression of Ucn 3 as well as Ucn 1 in the human heart. Ucn 3 is also expressed in the kidney, particularly distal tubules. Studies in various rat tissues showed that high concentrations of immunoreactive Ucn 3 were found in the pituitary gland, adrenal gland, gastrointestinal tract, ovary and spleen in addition to the brain, heart and kidney. These observations suggest that Ucn 3 is expressed in various tissues including heart and kidney, and may regulate the circulation in certain aspects of stress and diseases, such as inflammation. Ucn 1 and 3 appear to have important pathophysiological roles in some cardiovascular diseases.