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症例は58歳,男性,発熱を主訴に来院した.血液生化学検査では白血球増多およびCRPの上昇を認めた.腹部超音波にて肝S4を主座とする径6cm大のhaloを有するhypoechoicな腫瘤を認めた.腹部単純CTではLDA, 造影CTでは若干不均一に造影され,腹部MRIでは, T1でlow intensity, T2でhigh intensity,ガドリニウムによる造影では不均一に造影された.腹部血管造影では腫瘤はhypovascularであった.生検では肉腫の疑いであったが, inflammatory pseudotumorや転移性肝癌も否定できなかった.手術は肝中央2区域切除術を行った.病理組織所見では主として紡錘形の異型細胞からなり,免疫染色ではvimentinのみ陽性であったが,所々でsinusoidal patternがみられることより肉腫様変化を伴った肝細胞癌と診断された. 本疾患は術前診断が難しい上予後が極めて悪いため早期発見,早期手術が望まれる.

IFN-alpha was administered intermittently over a 6 month period in 39 patients with chronic non-A, non-B hepatitis confirmed by peritoneoscopy and liver biopsy. Three million units of IFN-alpha were administered 3 times a week for the first 6 months then twice, then once a week. In 26 patients (67%), GPT decreased and remained within the normal range during the course of administration, and in 9 patients (23%) GPT remained normal for over 6 months after the discontinuation of IFN-alpha. There was no significant difference of efficacy among 3 groups liver histology groups (CPH, CAH-2A, and CAH-2B), but GPT decreased significantly in patients with sporadic hepatitis compared to patients with a history of blood transfusion. Furthermore, GPT decreased significantly in patients with a history of a blood transfusion within the preceding 2 years compared to patients with a history of a blood transfusion over 7 years ago. GPT increased markedly after an early tapering to 2 doses weekly, but it did not increase after a 6 month administration. In conclusion, the long-term administration of 300 million unit IFN-alpha, 3 times weekly for 6 months, about 2.5 hundred million units in total, is thought to be an effective way to control chronic NANB hepatitis.

正常血圧の維持透析患考19名を, その基礎疾患から, 3群-慢性糸球体賢炎 (CGN)・糖尿病 (DM)・嚢胞腎 (PCK) に分け, 透析時の血圧変動と, その際の血漿レニン活性 (PRA), 血漿アルドステロン濃度 (PAC) の変動を検討した. DM群では, 透析中に他の2群に比較し, 著明な血圧下降 (43.7±19.3mmHg) がみられた. CGN群とPCK群には, 両者の問に, 血圧下降度において, 有意な差はみられなかった. また, DM群では, PRA基礎値は0.74±0.15ng/ml/hrと他の2群に比べ著しく低値 (p

To determine a role of norepinephrine (NE) in stress-induced HPA function, young male rats were treated with diethyldithiocarbamide (DDC) which inhibits dopamine-beta-hydroxylase, the enzyme that synthesizes NE from dopamine (DA). DDC injected 5 h prior to ether stress stimulated ACTH and corticosterone (B) during this time, and there was no further HPA response to ether. To control for elevated B feedback in DDC effects on HPA responses to ether, rats were adrenalectomized (Adx) and replaced with no (0% B), moderate (40% B) and high (80% B) levels of steroid 5 d prior to DDC or saline with ether stress 5 h later; Sham-Adx rats were included. In Adx rats increasing B inhibited thymus weight, median eminence CRF content, pituitary and plasma ACTH. In saline-treated rats, ether 5 h later caused increased CRF content and plasma ACTH in Sham-Adx and Adx, 0% B, increased ACTH in Adx, 40% B, and no response in Adx, 80% B. B treatment did not alter catecholamine content, and DDC treatment reduced NE content in the paraventricular nuclei by 50-60% in all groups. 5 h after DDC, pituitary ACTH was decreased in all rats with B and plasma ACTH was increased in sham-Adx and Adx, 40% B; thus DDC caused significant, prolonged stress which should facilitate subsequent HPA responses to acute stress. There was no HPA response to ether in Sham-Adx, Adx, 0% or 40% B groups, but there was a marked ACTH response to ether in the Adx, 80% B group treated with DDC. We conclude that: 1) the HPA response to ether stress is probably mediated by catecholamines; 2) DDC does not stimulate responses in the HPA axis in the absence of B; and, 3) facilitation of HPA responses to acute stress depends on increased steady-state B signals. Facilitated responses are probably not mediated by catecholamines. The consequence of facilitation is that under conditions of chronic stress and elevated B concentrations, as in depression or anorexia nervosa in man, or adjuvent-induced arthritis in rats, the HPA axis is continually responsive to new stimuli.

The effect of serine protease inhibitor Camostat Mesilate on nephrotic syndrome with diabetic nephropathy was evaluated. Eight patients with nephrotic syndrome associated with diabetic nephropathy were orally administered 600 mg of Camostat Mesilate per day. Three patients showed a reduction of urinary protein excretion promptly at 4 weeks. Serum protein and degree of edema improved significantly at 4 weeks. Camostat Mesilate had no effect on renal function assessed by creatinine clearance. During the observation period there were no significant changes in blood pressure, level of blood sugar, or HbA1c. Camostat Mesilate would be beneficial for the treatment of diabetic nephropathy.

Intravenous angiotensin II and ether stress were found to produce a rapid, transient increase in the corticotropin-releasing hormone (CRH) content of the median eminence as measured by a radioimmunoassay employing an antibody against rat CRH(1-41). This confirms previous reports of transient increases in CRH measured by bioassay. The increase did not occur in the paraventricular region or in other parts of the brain. It occurred along with an increase in plasma adrenocorticotropic hormone (ACTH) when a second ether stress was administered 1 h after the first, and it also occurred when rats that had been adrenalectomized for 5 days were exposed to ether. The increases in CHR and the ACTH responses to ether were reduced or abolished by dexamethasone and pentobarbital. Four days after semicircular knife cuts in the posterior hypothalamus, resting CRH in the median eminence was increased but there was no further rise after ether stress. Plasma ACTH was normal at rest after the cuts, but the increase produced by ether was reduced. The ACTH responses to angiotensin II and immobilization were also reduced. Because the posterior knife cuts reduced hypothalamic catecholamine content, the effects of reducing hypothalamic norepinephrine and epinephrine by administration of the dopamine-beta-hydroxylase inhibitor diethyldithiocarbamate (DDC) were tested. Five hours after DDC, plasma ACTH was elevated but there was no further increase with ether stress. The median eminence CRH content was normal but failed to increase after exposure to ether.(ABSTRACT TRUNCATED AT 250 WORDS)

A 51-yr-old male patient with a 3 yr history of Cushing's syndrome is described. The baseline plasma cortisol level was elevated, while the plasma ACTH levels remained at an undetectable level. Dynamic testing of pituitary-adrenal function revealed no suppression after 8 mg of dexamethasone, and there was no response to metyrapone or CRF, while plasma cortisol showed a hyperresponse to synthetic ACTH. Plasma cortisol responded to insulin-induced hypoglycemia without an obvious ACTH response. These and the computerized tomography data suggested a "huge" bilateral nodular adrenocortical hyperplasia which was later confirmed by surgery. The left and right adrenal glands weighed 55 and 76 g, respectively. In vitro experiments, using the adrenal tissue, showed that there was an adrenal cortisol response to 1-39 ACTH but not to regular insulin, arginine vasopressin, angiotensin II, norepinephrine or epinephrine. These results indicate that plasma cortisol responded to a slight hypoglycemia-induced plasma ACTH change which was not detected in the ACTH radioimmunoassay or to factors other than ACTH which might be induced by hypoglycemia.

This newly developed specific radioimmunoassay for corticotropin releasing factor (CRF) had a sensitivity range of 25 pg/tube to 4 ng/tube. Intra and interassay coefficient of variation were 4.6% and 9.8%, respectively. Rat median eminence extracts showed a parallel dose response curve with synthetic ovine CRF and a significant cross reaction was not evident with other tested neuropeptides. The highest mean levels of CRF were found in the median eminence (6.61 ng/mg protein). Considerable amounts of CRF were found in the arcuate nucleus, paraventricular nucleus, dorsomedial nucleus, suprachiasmatic nucleus and ventromedial nucleus. The immunoreactive CRF of the rat medial basal hypothalamus coeluted with bioassayable CRF and with iodinated CRF on Sephadex G-75 chromatography. The results indicate that rat hypothalamus contains a CRF similar to ovine CRF.

The effect of N-(6-aminohexyl)-5-chloro-naphthalene-l-sulfomide (W-7) and trifluoperazine (TFP) was examined on ACTH release from cultured rat anterior pituitary cells and pituitary halves. These drugs significantly inhibited the ACTH release induced by synthetic ovine corticotropin-releasing factor (CRF) in a dose-related manner. In pituitary halves, arginine vasopressin (AVP) at 10 and 100 ng/ml showed almost the same ACTH-releasing activity as CRF at the same concentrations. W-7 and TFP inhibited the CRF- and AVP-induced ACTH release from pituitary halves. The cyclic AMP levels in the pituitary halves were significantly increased by CRF, but not AVP. Although W-7 inhibited CRF-in-duced ACTH release, it did not have an effect in cyclic AMP accumulation. These results suggest that CRF exerts ACTH-releasing activity through both the calcium-calmodulin system and cyclic AMP system and that AVP stimulates ACTH release mainly through the calcium-calmodulin system.

Reversed-phase, high-performance liquid chromatography (HPLC) was carried out to characterize rat hypothalamic corticotropin-releasing factor (CRF) using synthetic ovine CRF as a marker. Samples were injected onto a stainless steel column (4 X 250 mm) packed with Hitachi gel 3053. The column was eluted using a gradient elution of increasing acetonitrile concentration, in a mixture of NaCl-HCl at a flow rate of 1.0 ml/min, monitoring the column effluent at 220 nm with an UV detector. Fractions eluted every 1-2 min were collected and lyophilized for subsequent CRF bioassay and radioimmunoassay. When various neuropeptide mixtures including synthetic ovine CRF were injected onto the column, synthetic ovine CRF was separated from the other neuropeptides with a gradient of 0-60% acetonitrile in 0.1 M NaCl-0.01 N HCl or 0-08% acetonitrile in 0.05 M NaCl-0.01 N HCl. The median eminence extracts showed two main peaks of CRF bioactivity on HPLC. One (small CRF) coeluted with arginine vasopressin and oxytocin markers, and the other (big CRF) appeared near the position of synthetic CRF and was divided into two peaks. One coeluted with synthetic ovine CRF and the second eluted after synthetic CRF, showing high CRF activity. Three or four peaks of CRF immunoreactivity appeared on HPLC and the main peak appeared after synthetic ovine CRF marker. Our results suggest that rat CRF is different from ovine CRF, and the total lipophilicity of amino acid residues of rat CRF may be higher than that of ovine CRF.

The effect of the synthetic ovine corticotropin-releasing factor (CRF) on adrenocorticotropin (ACTH) release was examined by the perifusion method using rat anterior pituitary tissue and rat monolayer cultured pituitary cells. Quartered anterior pituitaries were placed in a chamber and perifused at a rate of 400 microliters/min with Dulbecco's modified Eagle Medium (DMEM, pH 7.4) bubbled with a mixture of 95% O2 and 5% CO2. The perifused medium was fractionated, and the ACTH concentration was measured by radioimmunoassay. In the monolayer cultured pituitary cells, the amount of ACTH released in the culture medium during three hours incubation was assayed by radioimmunoassay. ACTH was released from the perifused anterior pituitary in a dose-related manner by the pulse administration of CRF or arginine vasopressin (AVP) at the concentration of 1 ng/ml, 10 ng/ml and 100 ng/ml. A significant difference was not found between CRF- and AVP-induced ACTH release. In the monolayer cultured pituitary cells, synthetic ovine CRF induced ACTH release in a dose-related manner between 30 pg/ml and 30 ng/ml, but AVP induced a slight ACTH release. ACTH release was pulsatile during the continuous administration of 2.5 ng/ml of CRF for 150 min, although if gradually increased during the continuous administration of 10 ng/ml or 20 ng/ml of CRF. The continuous administration of AVP also caused pulsatile ACTH release at 10 ng/ml, but the ACTH release gradually decreased during the continuous administration of AVP. The interaction between CRF and AVP on ACTH release was examined by two methods. When CRF and AVP were given simultaneously, a mainly additive effect on ACTH release was observed. However, a low concentration of CRF seemed to potentiate AVP-induced ACTH release. These results show that both CRF and AVP have a significant CRF activity on the perifusion system, that AVP induced a slight ACTH release in monolayer cultured pituitary cells, and that CRF acts additively or potently with AVP to control the ACTH release from the anterior pituitary gland.

Goat hypothalamic extract prepared by HCl extraction and chromatographed on a Sephadex G-50 column showed two immunoreactive CRF peaks. Most of the immunoreactivity coeluted with synthetic ovine CRF, and a small peak eluted near the void volume. Bovine, monkey, rat and human hypothalamic extracts prepared by acid-acetone or acid-methanol extraction showed three immunoreactive peaks. Most of the immunoreactivity coeluted with ovine CRF, and other smaller peaks eluted near the void volume and slightly before arginine vasopressin. Goat hypothalamic extract showed the highest cross-reactivity with anti-ovine CRF serum, followed by bovine hypothalamic extract. Less cross-reactivity was found in human, rat and monkey hypothalamic extracts. CRF immunoreactivity in goat hypothalamic extract coeluted with ovine CRF on reversed phase high performance liquid chromatography (HPLC) and main CRF immunoreactivity in human and rat hypothalamic extracts eluted slightly later than ovine CRF. These results suggest that there is a heterogeneity among the CRF molecules in these species and that goat CRF may be more similar to that of sheep CRF and the amino acid sequence or molecular weight of other animals CRF may be different from that of sheep CRF. The monkey posterior pituitary and rat neurointermediate lobe showed similar elution patterns of CRF immunoreactivity to their hypothalamic extracts on Sephadex gel filtration and HPLC. These results indicate that the posterior pituitary contains a similar CRF to hypothalamic CRF.

The effect of nifedipine on CRF-41- and AVP-induced ACTH release was examined using monolayer cultured rat anterior pituitary cells and pituitary halves. Nifedipine inhibited ACTH release induced by synthetic rat CRF-41 in two systems. In pituitary halves, CRF-41 significantly stimulated both ACTH release and cyclic AMP accumulation. Nifedipine inhibited CRF-41-induced ACTH release and the inhibitory effect of nifedipine on CRF-41-induced ACTH release was accompanied by parallel decrease of cyclic AMP levels in pituitary halves. Nifedipine did not inhibit AVP-induced ACTH release in pituitary halves, and AVP did not significantly affect cyclic AMP accumulation in pituitary halves. These results suggest that CRF-41 stimulates ACTH release through the intracellular cyclic AMP system and calcium-calmodulin system which are accelerated by the influx of extracellular calcium ions. Moreover, it is suggested that the calcium required for AVP-induced ACTH release is derived primarily from intracellular rather than extracellular sources.

To investigate the site at which angiotensin II (AII) acts to increase adrenocorticotrophic hormone (ACTH) secretion, the effects of intraventricular (IVT) or intravenous (IV) injection of the AII antagonist saralasin on the ACTH responses to IVT or IV injection of AII were examined in conscious male rats. AII does not cross the blood-brain barrier, but IVT as well as IV saralasin are known to prevent the binding of circulating AII to circumventricular organs. IV AII (0.2-200 ng) induced dose-related increases in ACTH secretion and a transient increase in the corticotrophin-releasing hormone (CRH) content of the median eminence. IVT injection of saralasin (10 micrograms) blocked the ACTH responses to IV AII. The same dose of saralasin given intravenously did not produce a comparable decrease in the ACTH response to IV AII. IVT injection of 1 and 10 ng AII increased plasma ACTH in a dose-related manner. The increase in plasma ACTH induced by IVT administration of angiotensin was not inhibited by IV infusion of saralasin (12 micrograms/kg/min). On the other hand IV infusion of this dose of saralasin abolished or reduced the ACTH response to IV injection of larger doses of AII. These data support the conclusion that circulating AII stimulates ACTH secretion by acting on the circumventricular organs to increase CRH secretion. They also suggest that AII receptors inside the blood-brain barrier as well as AII receptors in the circumventricular organs trigger increases in ACTH secretion.

1. In rats and in at least some other species, IV and IVT AII stimulate ACTH secretion. 2. Although AII increases ACTH secretion by a direct action on pituitary cells in vitro, it appears to act instead by stimulating CRH secretion in vivo. 3. The CRH stimulating effect of circulating AII is mediated by an action of the AII on one or more of the circumventricular organs of the brain. 4. AII administered into the cerebral ventricles and, presumably, centrally generated AII, increase CRH secretion by acting on AII receptors inside the blood-brain barrier as well as in the circumventricular organs. 5. A possible role for the renin-angiotensin system in mediating the increase in ACTH secretion produced by stress has been suggested, and the degree of involvement may vary from one stress to another. However, as yet we have been unable to obtain any evidence that either circulating AII or centrally generated AII plays a role in the increase in ACTH secretion produced by ether stress in rats and surgical stress in dogs.

Abnormalities in the hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats (SHR) during development of hypertension were investigated using in vivo and in vitro methods. Plasma ACTH responses to hemorrhage and ether stress were significantly smaller in 7-week-old SHR than in age-matched Wistar-Kyoto rats (WKY), while plasma corticosterone baseline levels and its response to stress were greater in SHR than in WKY. There was no significant difference in the plasma ACTH response to ether stress between bilaterally adrenalectomized SHR and WKY replaced with a 25% corticosterone pellet for 6 days. Adrenalectomy prevented the development of hypertension in SHR; however, corticosterone replacement restored hypertension. Plasma ACTH showed a smaller response to iv CRH injection in SHR than in WKY, while the ACTH response to arginine vasopressin was not different between SHR and WKY. CRH concentrations in the median eminence, posterior pituitary, and cerebral cortex were lower in SHR than in WKY, while the CRH concentration in the median eminence was not different in SHR and WKY when they were adrenalectomized with or without corticosterone replacement. Basal in vitro CRH release from hypothalamic tissue was reduced in SHR, while CRH release in response to 56 mM KCl was not different in SHR and WKY. These results suggest that adrenocortical function is enhanced in young SHR, that reduced ACTH response to stress and exogenous CRH in SHR may be ascribed to higher plasma corticosterone levels, and that corticosterone is essential for the development of hypertension in SHR.

Effects of 1-(m-trifluoromethylphenyl)-piperazine, a serotonin agonist, were examined on rat plasma levels of adrenocorticotropin (ACTH) and arginine vasopressin (AVP), and on hypothalamic contents of corticotropin releasing factor (CRF) and AVP, to investigate the role of brain serotonin in ACTH regulation. Both plasma ACTH and AVP levels increased markedly 30 min after injection of the compound and were still elevated at 80 min. CRF and AVP contents in the median eminence decreased 30 min after injection but returned to the basal levels by 80 min. The AVP content in the supraoptic nucleus was elevated 80 min after injection. The CRF and aVP content did not significantly change in the paraventricular, suprachiasmatic and arcuate nuclei. Serotonin or 1-(m-trifluoromethylphenyl)-piperazine did not stimulate the release of ACTH in pituitary cell cultures. These results suggest that both CRF and AVP were secreted into the portal vessels by 1-(m-trifluoromethylphenyl)-piperazine to release ACTH from the anterior pituitary and that both the ACTH and AVP release were stimulated via the brain serotonergic mechanism.

Synthetic ovine corticotropin releasing factor (CRF) at 0.03–30 ng/ml evoked a significant linear release of ACTH in pituitary monolayer cell cultures. Arginine vasopressin (AVP) at 3–30 ng/ml induced a slight ACTH release in the same culture system. CRF at 100 ng/ml greatly increased the medium ACTH with intracellular ACTH remaining relatively constant. In perifused pituitary quarters, both AVP and CRF evoked significant release of ACTH. When AVP was added in combination with synthetic ovine CRF, an additive or synergistic effect was observed on the CRF-induced ACTH release in both in vitro systems. Preincubation of cultured pituitary cells with synthetic ovine CRF for 1 h did not have a significant effect on the subsequent AVP-induced ACTH release. However, when cells were preincubated for 6 h with CRF at 1 and 100 ng/ml, the AVP-induced ACTH release was significantly increased, but preincubation with AVP suppressed both the basal and AVP-induced ACTH release. These results suggest that synthetic ovine CRF stimulates not only the release of ACTH but also the synthesis of ACTH and that AVP can evoke significant ACTH release from corticotrophs which have enough releasable ACTH or substances needed for ACTH release under the influence of CRF.

Plasma ACTH increased after an intra-third ventricular administration of noradrenaline (NA). An iv corticotrophin-releasing factor (CRF) antagonist [alpha-helical CRF(9-41)] injection did not affect ACTH secretion by itself, whereas it significantly reduced NA-induced ACTH secretion. These results suggest that NA centrally stimulated ACTH secretion and that endogenous CRF is involved in this ACTH secretion.