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We previously reported that immunoreactive corticotropin-releasing hormone (CRH) is present in human placenta and third trimester maternal plasma, and that such material is very similar to rat CRH and the predicted structure of human CRH. We suggested that maternal plasma immunoreactive CRH may be of placental origin. To further investigate this possibility, we measured plasma immunoreactive CRH in women during pregnancy, labor, and delivery and 1 and 2 h postpartum, and in nonpregnant women. Umbilical cord plasma and placental CRH concentrations were also measured. In the first trimester of pregnancy, the mean maternal plasma level was 5.9 +/- 1.0 pg (+/- SEM)/ml (n = 24), not significantly different from that in 10 nonpregnant women (5.8 +/- 0.8 pg/ml). Plasma CRH concentrations progressively increased during pregnancy (second trimester, 35.4 +/- 5.9 pg/ml (n = 39); early third trimester (28-34 weeks), 263 +/- 41 pg/ml (n = 14); late third trimester (35-40 weeks), 800 +/- 163 pg/ml (n = 20)]. There was a significant correlation between maternal plasma CRH levels and weeks of pregnancy. Plasma CRH concentrations were further elevated (2215 +/- 329 pg/ml; n = 9). During early labor, peaked at delivery (4409 +/- 591 pg/ml; n = 28), and declined rapidly after delivery [1 h postpartum, 1042 +/- (353 pg/ml (n = 13); 2 h postpartum, 346 +/- 91 pg/ml (n = 13)]. There was a significant correlation (r = 0.562; P less than 0.01) between matched maternal plasma and placental CRH concentrations. The mean umbilical cord plasma CRH level (50.6 +/- 6.1 pg/ml; n = 28) was much lower than that in the mother at the time of delivery. Umbilical venous plasma CRH levels were significantly greater than those in simultaneously obtained umbilical arterial plasma (70.8 +/- 11.3 and 41.8 +/- 4.9 pg/ml, respectively; n = 11). There was a significant correlation (r = 0.384; P less than 0.05) between maternal and fetal CRH concentrations. Gel filtration of plasma obtained from women during the third trimester, at delivery, and early postpartum and placental extracts revealed two major peaks of immunoreactive CRH: a high mol wt peak and one at the elution position of rat CRH. In contrast, only rat CRH-sized material was detected in plasma from nonpregnant women and umbilical cord plasma. Maternal plasma immunoreactive CRH-sized material stimulated ACTH release from anterior pituitary tissue in a dose-dependent manner and was equipotent with rat CRH.(ABSTRACT TRUNCATED AT 400 WORDS)

Abstract. 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.

SUMMARYThe circadian blood pressure rhythm was compared in patients with Cushing's syndrome, essential hypertension, and primary aldosteronism. In patients with essential hypertension or primary aldosteronism, a dear nocturnal fall hi systolic and diastolk blood pressure and heart rate was observed. This fall was seen in untreated subjects as well as hi patients receiving combined treatment with a calcium antagonist, diuretic, converting enzyme inhibitor, a-blocker and 0-blocker, or sympatholytic drug. In these groups, there was a positive correlation between heart rate and systolic or diastolic blood pressure. On the other hand, hi patients with Cushing's syndrome, there was no nocturnal fall hi blood pressure but in some patients a rise was observed. In all patients there was a nocturnal fall hi heart rate. Thus, there was no significant correlation between heart rate and blood pressure hi these patients. Exogenous glucocortkoid eliminated the normal nocturnal fall of blood pressure hi patients with chronic glomerulonephritis or systemic lupus erythematosus. These results suggest that the changed circadian blood pressure pattern hi patients with Cushing's syndrome is not due to antihypertensive treatment or to the mineralocorticold excess accompanying this disease, but it is attributable to excess glucocorticoid or the associated disturbance hi the adrenocorticotropic hormone-glucocorticoid system (or both). This conclusion also implies that the normal circadian rhythm of blood pressure may be regulated at least in part by the adrenocorticotropic hormone -glucocorticoid system. and it has been shown that BP reaches a nadir at approximately 0300, begins to rise again at 0500, and reaches its highest level at about 0900. The latter increase is said not to be associated with physical activity.1 Several researchers have claimed that the fluctuations observed in BP are related to daily activities such as sleep and physical exertion 2 -5 rather than the presence of an independent BP

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A B S T R A C TUrotensin II (UII) is the most potent vasoconstrictor peptide, whereas it acts as a vasodilator on some arteries. We studied plasma levels of UII in diabetic patients with normal serum creatinine levels ( 90 µmol/l) and the expression of UII and its receptor in cultured human vascular endothelial cells. Plasma UII levels were significantly elevated by 1.8-fold in diabetic patients without proteinuria (7.8p0.6 fmol/ml ; P 0.0001) and 1.7-fold in those with overt proteinuria (7.3p0.9 fmol/ml ; P l 0.0018) when compared with healthy subjects (4.4p0.2 fmol/ml). No significant correlation was obtained between plasma UII levels and fasting blood sugar (P l 0.631 and P l 0.853 in non-proteinuric and proteinuric diabetic patients respectively), glycated haemoglobin levels (P l 0.376 and P l 0.888 respectively) or serum creatinine levels (P l 0.301 and P l 0.568 respectively). Reverse transcriptase-PCR analysis showed the expression of mRNAs encoding UII precursor and UII-receptor precursors in cultured human coronary artery endothelial cells and umbilical vein endothelial cells, suggesting that vascular endothelial cells are one of the sources of UII in blood. These findings suggest that elevation of plasma UII levels may be an important background factor in diabetic cardiovascular and organ complications in diabetic subjects without renal failure.

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.

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