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Makoto Kobayashi, Eiji Yoshida, Takuro Kyuno, Ryoko Kawagishi, Kei Sato, Tsuyoshi Kono, Takehiro Chiba, Hitoshi Yonezawa, Osamu Funato, Akinori Takagane Department of Surgery, Hakodate Goryoukaku Hospital, Hakodate City, Hokkaido, 040-8611, JapanCorrespondence: Makoto KobayashiDepartment of Surgery, Hakodate Goryoukaku Hospital, 38-3 Goryoukaku-cho, Hakodate City, Hokkaido, 040-8611, JapanTel +81-138-51-2295Fax +81-138-56-2696Email koba86gg@gmail.comPurpose: Faster surgery has been associated with better outcomes. In the present study, we aimed to determine whether surgical duration affected overall survival (OS) in patients undergoing esophagectomy. Additionally, we assessed factors that influence surgical duration.Patients and Methods: This single-center retrospective cohort study included 128 patients who underwent Ivor-Lewis esophagectomy by a single surgeon between 2005 and 2019. The Cox proportional hazard model was used to evaluate the association of OS with the following variables: surgical duration, neo-adjuvant chemotherapy, pathological grade of depth of tumor invasion, lymph node (LN) metastasis, body mass index (BMI), and cervical LN dissection. Additionally, factors associated with prolonged surgical duration were examined by logistic regression analysis.Results: Based on the multivariate analysis, surgical duration was not associated with OS [hazard ratio (HR), 1.065; 95% confidence interval (CI), 0.586– 1.937; P = 0.837]. On the other hand, tumor invasion (HR, 2.901; 95% CI, 1.483– 5.674; P = 0.002) and LN metastasis (HR, 2.338 2.403; 95% CI, 1.237– 4.420 1.257– 4.593; P = 0.009 0.008) significantly influenced OS. The assessment of variables affecting surgical duration showed that BMI had a significant effect on surgical duration (odds ratio, 2.790; 95% CI, 1.254– 6.204, P = 0.012).Conclusion: According to the analysis of patients who underwent the same surgical approach by a single surgeon, surgical duration of esophagectomy for esophageal cancer was significantly influenced by BMI; however, surgical duration had no impact on patient survival.Keywords: esophagectomy, Ivor-Lewis approach, depth of tumor invasion, lymph node metastasis, body mass index, overall survival

Hiroshi Yamaguchi,1 Yasutoshi Kimura,1 Masafumi Imamura,1 Minoru Nagayama,1 Tatsuya Ito,1 Daisuke Kyuno,1 Tsuyoshi Kono,1 Akina Kimura,1 Emi Akizuki,1 Toshihiko Nishidate,1 Kenji Okita,1 Takayuki Nobuoka,1 Toru Mizuguchi,1,2 Koichi Hirata,3 Ichiro Takemasa1 1Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan; 2Department of Nursing and Surgical Science, Sapporo Medical University School of Health Science, Sapporo, Japan; 3Department of Surgery, JR Sapporo Hospital, Sapporo, JapanCorrespondence: Hiroshi YamaguchiDepartment of Surgery, Surgical Oncology and Science, Sapporo Medical University, South 1, West 16, Sapporo 060-8543, JapanTel +81 11-611-2111 Ext 32810Fax +81 11-613-1678Email hyama@sapmed.ac.jpIntroduction: Delayed gastric emptying (DGE) remains an important problem after pancreaticoduodenectomy (PD). There is a lack of effective treatments for early recovery of oral dietary intake. Rikkunshito (RKT), a Japanese herbal medicine, has been gaining attention as a facilitator of gastric emptying. We evaluated the effects of RKT on DGE after PD.Methods: In this prospective, randomized, open-labeled study, patients were randomly allocated before PD in a 1:1 ratio to the RKT group or the control group that received no additional treatment. The RKT group received 2.5 g of RKT three times daily (7.5 g/day) from postoperative day (POD) 1 to POD 21. The primary endpoint was the incidence of DGE. Secondary endpoints were short-term postoperative outcomes including oral dietary intake volume and perioperative changes in levels of the hormones ghrelin and leptin. Patients were observed until hospital discharge.Results: Twenty-six patients in each group (n = 52) completed the protocol treatment and were included in the analysis set. There were no statistically significant differences in basic characteristics and operative factors. The overall incidence of DGE was not statistically different between the RKT and control groups (30.8% vs 30.8%, p> 0.9999). There were no statistically significant differences in the amount of postoperative oral dietary intake represented by total dietary intake (TDI) up to POD 14 and POD 21, complications, and length of hospital stay. No adverse events related to this study were observed. In the RKT group, total ghrelin and acyl-ghrelin were significantly upregulated and leptin was significantly downregulated earlier than in the control group.Conclusion: RKT treatment from POD 1 to 21 did not reduce the incidence of DGE and had no clinically beneficial effect on short-term postoperative outcomes irrespective of changes in hormone levels.Keywords: delayed gastric emptying, pancreaticoduodenectomy, Rikkunshito, ghrelin, leptin

Purpose Early management is crucial for acute intestinal blood flow disorders; however, no published study has identified criteria for the time limit for blood flow resumption. This study specifically examines the time factors for avoiding intestinal resection. Methods The subjects of this retrospective cohort study were 125 consecutive patients who underwent emergency surgery for a confirmed diagnosis of intestinal strangulation (n = 86), incarceration (n = 27), or volvulus (n = 12), between January 2015 and March 2021. Intestinal resection was performed when intestinal irreversible changes had occurred even after ischemia was relieved surgically. We analyzed the relationship between the time from computed tomography (CT) imaging to the start of surgery (C-S time) and intestinal resection using the Kaplan–Meier method and calculated the estimated intestinal rescue rate. Patient background factors affecting intestinal resection were also examined. Results The time limit for achieving 80% intestinal rescue rate was 200 min in C-S time, and when this exceeded 300 min, the intestinal rescue rate dropped to less than 50%. Multivariate analysis identified the APACHE II score as a significant influencing factor. Conclusion A rapid transition from early diagnosis to early surgery is critical for patients with acute abdomen originating from intestinal blood flow disorders. The times from presentation at the hospital to surgery should be reduced further, especially for severe cases.

Delayed gastric emptying (DGE) is a relatively common complication after pancreatoduodenectomy (PD). The aim of this study was to determine whether DGE is affected by antecolic or retrocolic reconstruction for gastro/duodenojejunostomy after PD.A literature search was performed of the MEDLINE (PubMed), Ovid SP, ISI Web of Knowledge, EMBASE, and Cochrane databases to identify randomized controlled trials (RCTs) and clinical observational studies related to this topic from January 1995 to November 2014. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for categorical outcomes, and mean differences (MD) using fixed-effect and random-effects models were calculated for the meta-analysis.Fourteen studies including 1969 patients met the inclusion criteria. Six studies were RCTs, and eight studies were clinical observational studies. DGE was less common in the antecolic reconstruction group than in the retrocolic reconstruction group (OR = 0.24 [0.12-0.48], P 0.0001). Postoperative days to start solid foods (MD = -3.67 d [-5.10 to -2.33], P 0.00001) and length of hospital stay (MD = -2.90 d [-5.36 to -2.33], P 0.00001) were also significantly in favor of the antecolic reconstruction group. There was no difference in the incidence of pancreatic fistula, intra-abdominal fluid collection or abscess, biliary fistula, or mortality. However, in the subgroup analyses, using the data of six RCTs or seven studies according to the International Study Group of Pancreatic Surgery definition, there was no significant difference in the incidence of DGE.Antecolic reconstruction for gastro/duodenojejunostomy does not seem to offer an advantage over retrocolic reconstruction with respect to DGE after PD.

Our recent work revealed that elevated expression of claudin-18 is involved in bile duct neoplasia. In the present study, we found that wound generation of a cell sheet de novo induced claudin-18 expression in its leading edge, coincident with high mitotic activity. We also found that the suppression of claudin-18 expression significantly reduced cell growth and invasiveness of bile duct cancer cell lines and tumorigenicity in vivo. In addition, an antibody specific to an extracellular loop of claudin-18 showed similar effects on the cells such as cell proliferation. Interestingly, treatment with epidermal growth factor (EGF) and overexpression of RAS oncogene induced claudin-18 expression by activation of extracellular signal-related kinase (ERK)1/2. Furthermore, enhanced claudin-18 expression activated ERK1/2. These findings provide evidence for an oncogenic property of claudin-18 in bile duct carcinoma cells via modulation of EGFR/ERK signaling, indicating that claudin-18 is a possible therapeutic target for this malignancy.

Accumulating evidence has shown that dysregulation of tight junctions (TJs) is involved in tumor development and progression. In this study, we investigated the expression and subcellular distribution of tricellulin, which constitutes tricellular TJs, using human pancreatic adenocarcinomas. In well-differentiated pancreatic adenocarcinoma tissues, tricellulin immunostaining was prominent in the cytoplasm and the plasma membrane. In contrast, in poorly differentiated tissues, its immunostaining was predominantly observed in the nuclei and was almost absent in the plasma membrane. The distinct immunostaining of tricellulin successfully distinguished poorly differentiated adenocarcinoma from moderately and well-differentiated adenocarcinomas with high levels of sensitivity and specificity. Nuclear tricellulin expression significantly correlated with lymph node metastasis, lymphatic invasion and poor survival. In pancreatic cancer cell lines, tricellulin localization shifted from the membrane to nucleus with decreasing differentiation status. Nuclear localization of tricellulin promoted cell proliferation and invasiveness possibly in association with MAPK and PKC pathways in pancreatic cancers. Our results provide new insights into the function of tricellulin, and its nuclear localization may become a new prognostic factor for pancreatic cancers.

The C‐terminal fragment of Clostridium perfringens enterotoxin (C‐CPE) modulates the tight junction protein claudin and disrupts the tight junctional barrier. It also can enhance the effectiveness of anticancer agents. However, the detailed mechanisms of the effects of C‐CPE remain unclear in both normal and cancerous cells. The C‐CPE mutant called C‐CPE 194 binds only to claudin‐4, but the C‐CPE 194 mutant called C‐CPE m19 binds not only to claudin‐4 but also to claudin‐1. In the present study, to investigate the mechanisms of the effects of C‐CPE on claudin expression, the tight junctional functions and the cytotoxicity of anticancer agents, human pancreatic cancer cells, and normal human pancreatic duct epithelial cells (HPDEs) were treated with C‐CPE 194 and C‐CPE m19. In well‐differentiated cells of the pancreatic cancer cell line HPAC, C‐CPE 194 and C‐CPE m19 disrupted both the barrier and fence functions without changes in expression of claudin‐1 and ‐4, together with an increase of MAPK phosphorylation. C‐CPE 194, but not C‐CPE m19, enhanced the cytotoxicity of the anticancer agents gemcitabine and S‐1. In poorly differentiated pancreatic cancer cell line PANC‐1, C‐CPE 194, but not C‐CPE m19, decreased claudin‐4 expression and enhanced MAPK activity and the cytotoxicity of the anticancer agents. In normal HPDEs, C‐CPE 194 and C‐CPE m19 decreased claudin‐4 expression and enhanced the MAPK activity, whereas they did not affect the cytotoxicity of the anticancer agents. Our findings suggest that the claudin‐4 binder C‐CPE 194 enhances effects of anticancer agents on pancreatic cancer cell lines via a MAPK pathway.

症例は83歳，男性．転倒による骨折を契機に入院し骨接合術を施行，リハビリテーション中であったが2週後に高熱と下血をきたした．絶食と抗生剤の投与を施行したが症状が改善せず，内視鏡検査でS状結腸に限局した全周性の浮腫，充血を認め，また生検で核内封入体が認められたためサイトメガロウイルス（以下CMV）腸炎と診断された．ガンシクロビルが投与されたが，下血が続き病変部の狭窄が進行したために当科で同部位の切除を行った．切除標本では明らかな虚血の所見はなく，粘膜下に核内封入体を認めた．術前血中のCMV antigenemiaは陽性だったが術後は陰性化した．元来健康な高齢者ではあったが一時的な免疫能低下によってCMV腸炎をきたしたものと考えられた．

Tight junctions of the pancreatic duct are essential regulators of physiologic secretion of the pancreas and disruption of the pancreatic ductal barrier is known to contribute to the pathogenesis of pancreatitis and progression of pancreatic cancer. Various inflammatory mediators and carcinogens can trigger tight junction disassembly and disruption of the pancreatic barrier, however signaling events that mediates such barrier dysfunctions remain poorly understood. This review focuses on structure and regulation of tight junctions in normal pancreatic epithelial cells and mechanisms of junctional disruption during pancreatic inflammation and cancer. We will pay special attention to a novel model of human telomerase reverse transcriptase-transfected human pancreatic ductal epithelial cells and will describe the roles of major signaling molecules such as protein kinase C and c-Jun N-terminal kinase in formation and disassembly of the pancreatic ductal barrier.

Basal and insulin-stimulated neutral glyceride syntheses from glucose were studied in fat cells of different size (fat cell volume, 0.07-0.20, 0.20-0.60, 0.60-1.00, 1.00-1.50 micron3 X 10(6)) obtained from subcutaneous adipose tissues in 20 subjects aged 3 months to 67 years. In 0.07-0.20 or 0.20-0.60 micron3 X 10(6) fat cells, the basal rate of glucose conversion to neutral glyceride was significantly lower in mature (36 to 67 years old) than in growing (0 to 12 years old) subjects. In 0.60-1.00 or 1.00-1.50 micron3 X 10(6) fat cells, however, basal rate was not significantly different between the two groups. The stimulating effect of insulin on conversion of glucose to neutral glyceride was not significantly different from the basal rate in fat cells of each size taken from the mature subjects, whereas in fat cells from growing subjects, it was significantly different from the basal rate in each fat cell size category. These results indicate that when fat cell size is taken into account, not only is the rate of basal glucose conversion to neutral glyceride higher in growing subjects but also its responsiveness to exogenous insulin, and that insulin insensitivity of large fat cells, reported previously, may be influenced by age.

Pancreatic cancer continues to be a leading cause of cancer-related death worldwide and there is an urgent need to develop novel diagnostic and therapeutic strategies to reduce the mortality of patients with this disease. In pancreatic cancer, some tight junction proteins, including claudins, are abnormally regulated and therefore are promising molecular targets for diagnosis, prognosis and therapy. Claudin-4 and -18 are overexpressed in human pancreatic cancer and its precursor lesions. Claudin-4 is a high affinity receptor of Clostridium perfringens enterotoxin (CPE). The cytotoxic effects of CPE and monoclonal antibodies against claudin-4 are useful as novel therapeutic tools for pancreatic cancer. Claudin-18 could be a putative marker and therapeutic target with prognostic implications for patients with pancreatic cancer. Claudin-1, -7, tricellulin and marvelD3 are involved in epithelial to mesenchymal transition (EMT) of pancreatic cancer cells and thus might be useful as biomarkers during disease. Protein kinase C is closely related to EMT of pancreatic cancer and regulates tight junctions of normal human pancreatic duct epithelial cells and the cancer cells. This review focuses on the regulation of tight junctions via protein kinase C during EMT in human pancreatic cancer for the purpose of developing new diagnostic and therapeutic modalities for pancreatic cancer.

s / Pancreatology 13 (2013) S1–S80 S17 down-regulation of Bcl-2 or Bcl-xL protein expression had a much weaker effect on PaCa apoptosis. Surprisingly, simultaneous knock-down of BclxL and Mcl-1 induced apoptosis strongly. However, simultaneous knockdown of Bcl-xL and Bcl-2 or Mcl-1 and Bcl-2 had no additive effect. The apoptosis inducing effect of simultaneous knock-down of Bcl-xL and Mcl1 is associated with Bax activation, mitochondrial cytochrome c release, and caspase cascade. Furthermore, the apoptosis-inducing effect of simultaneous knock-down of Bcl-xL and Mcl-1 was confirmed in animal model. Conclusions: These data suggest Bcl-xL and Mcl-1 as a potential therapeutic target for PaCa treatment and may help to develop novel therapeutic strategies for PaCa cells.

In 10 cases of Bartter's syndrome, plasma active and inactive renin (AR and IR) were measured by two different methods. First, plasma renin activity (PRA), and total renin activity (TRA) after activating IR with trypsin, were measured by radioimmunoassay (RIA) of angiotensin I (AI) generated from endogenous substrate. And secondly, plasma active renin concentration (ARC) and total renin concentration (TRC) were measured by RIA of AI generated in the presence of an excess of exogenous substrate. The difference between TRA and PRA, and between TRC and ARC were designated as inactive renin activity (IRA) and inactive renin concentration (IRC), respectively. Small amounts of IRA were found only in 2 cases and no IRA in 8 cases. However, the existence of large amounts of IR in Bartter's syndrome was revealed by the IRC determination. This suggests that the shortage of endogenous renin substrate, consumed by the markedly increased AR, may have interfered with the detection of IRA in Bartter's syndrome, though the IR is markedly increased as well. The molecular weights of AR and IR were determined by Sephadex G-100 gel filtration in 3 cases. Both AR and IR seemed to be smaller than those of normal subjects.

Biological activity of ileu8-angiotensin III (AIIIA) was studied in man. In 5 normal men intravenous infusion of 200 ng/kg/min of AIIIA for 30 minutes from 0900 h had no effect on blood pressure (BP) but caused a decrease in plasma renin activity (PRA) and an increase in plasma aldosterone (PA). This dose did not inhibit pressor and steroidogenic actions of angiotensin II (AII) infused into the normal men at a rate of 20 ng/kg/min for 30 minutes. In 3 patients with Bartter's syndrome 260-1,200 ng/kg/ min of AIIIA infusion for 30 minutes from 0900 h had no effect on BP but caused decreases in PRA and PA. These results indicate that in man AIIIA has no pressor action and no antagonistic effect on pressor action of AII but has PRA-lowering and aldosterone-stimulating effects. Antagonistic effect of AIIIA on steroidogenic action of AII was also shown in patients with Bartter's syndrome but not in AII-treated normal men. This may be due to the difference of administered dose of AIIIA.

When des-(Asp 1 , Arg 2 , Val 3 )-angiotensin II was infused iv at rates of 308–5,550 pmol/kg·min for 10–120 min into 5 normal men and 2 patients with Bartter's syndrome, no significant change was observed in blood pressure (BP), plasma renin activity (PRA) or plasma aldosterone (PA), and the lowest dose did not inhibit a captopril-induced increase in PRA in the normal men, although des-(Asp 1 , Arg 2 )-angiotensin II was reported in the same 5 normal men to cause a decrease in PRA and an increase in PA in this dose range and a rise in BP at 2,220 and 5,550 pmol/kg·min. However, an iv infusion of the pentapeptide at 9,000 pmol/kg·min for 15 min significantly raised BP in the 5 normal men but not in patients with Bartter's syndrome. BP returned to the pretreatment level 60 min after the cessation of the infusion, although the duration of the pressor actions of angiotensin II, angiotensin III and des-(Asp 1 , Arg 2 )-angiotensin II were reported to be within 5 min in man. At the same dose level none of the 7 examined subjects showed any significant change in PRA or PA. Des-(Asp 1 , Arg 2 , Val 3 , Tyr 4 )-angiotensin II was infused iv at a rate of 41,480 pmol/kg·min into one of the normal men, but it caused no significant change in BP, PRA or PA. These results suggest that the pentapeptide and probably the tetrapeptide do not possess renin-suppressing and steroidogenic actions in man but the pentapeptide does elecit a minimal pressor action with a prolonged duration.

In 5 normal men sarcosine1-angiotensin II (Sar1-ANG II) (Exp. 1) and sarcosine1-angiotensin I (Sar1-ANG I) (Exp. 2) infused iv at a rate of 5 pmol/kg X min from 0900 h to 0930 h caused the same degree of rise in blood pressure (BP). But 100 mg of captopril given orally at 0800 h (Exp. 3) completely abolished the BP rise by Sar1-ANG I. In Exps. 1 and 2 plasma renin activity (PRA) decreased and plasma aldosterone (PA) increased after the infusions. In Exp. 3 PRA increased markedly and PA decreased 60 min after captopril, and at 30 min of Sar1-ANG I infusion PRA decreased to the pre-captopril level despite no BP change but PA was kept at the pre-infusion level. Hence, substrate specificity of converting enzyme previously demonstrated for N-terminal deleted ANG I was not shown for N-terminal substituted ANG I in man because the conversion of Sar1-ANG I to Sar1-ANG II was 100%. Sar1-ANG I may possibly inhibit renin release in normal men.

The biological activity of high doses of des-asp1-,ileu8-angiotensin II (AIIIA) was studied in man. In 5 normal men an intravenous infusion of 600 ng/kg/min of AIIIA for 30 min caused a slight rise in blood pressure, a decrease in plasma renin activity and an increase in plasma aldosterone. This dose inhibited pressor and steroidogenic actions of angiotensin II infused into the same 5 normal men at a rate of 20 ng/kg/min for 30 min. These results are considerably different from our previous report using lower dose (200 ng/kg/min) of AIIIA and indicate that in man AIIIA has both agonist and antagonist activities on the peripheral arterioles as well as on the adrenal cortex.

各種副腎疾患およびその他計20例について, 131I-adosterolによる副腎シンチグラフィを施行した。原発性アルドステロン症の鑑別診断および部位決定に, クッシング症候群の鑑別診断, 部位決定および過形成症例の下垂体照射後の経過観察に, 褐色細胞腫および後腹膜腫瘍の患側決定および副腎への浸潤の有無の判定に, 副腎シソチは有用であった。ことに原発性アルドステロン症の場合, 腺腫が小さいことが多いため, dexamethasone suppressionシンチがきわめて有用であり, standardシンチにて病側決定が困難であった3例の局在診断が可能となった。

In order to clarify the importance of C-terminal phenylalanine in angiotensin II (ANG II) molecule, agonistic activities of a C-terminal substituted peptide, isoleucine8-angiotensin II (Ile8-ANG II), were studied in comparison with those of sarcosine1-, isoleucine8-angiotensin II (Sar1-, Ile8-ANG II) and isoleucine5-angiotensin II (Ile5-ANG II) in 5 normal men. When infused iv at a rate of 600pmol/kg·min for 30min, Ile8-ANG II and Sar1-, Ile8-ANG II raised the blood pressure to the same extent (15/15mmHg on the average), while the average blood pressure increase was 21/21mmHg after an iv infusion of Ile5-ANG II at a rate of 5pmol/kg·min for 30min. Duration of the pressor action after the cessation of each infusion was 50-90, 90-120 and 10-25min, respectively. In each case plasma renin activity (PRA) decreased and plasma aldosterone (PA) increased. When infused iv at a rate of 10 pmol/kg·min (maximum non-pressor dose) for 120min, both Ile8-ANG II and Sar1-, Ile8- ANG II lowered PRA and increased PA gradually, but 100mg oral captopril given immediately before these infusions caused no significant increase in PRA or no significant decrease in PA but again a decrease in PRA and an increase in PA. These results indicate that Ile8-ANG II has a very weak pressor (less than 0.83% of Ile5-ANG II and same as Sar1-, Ile8-ANG II) and slight reninsuppressing and steroidogenic actions in man and its metabolic degradation is slower than that of Ile5-ANG II and that the substitution of sarcosine for aspartic acid in the N-terminus of Ile8-ANG II further slows its metabolism. It is now evident that phenylalanine in 8 position is very important in maintaining sufficient pressor, renin-supressing and steroidogenic actions of ANG II but that this amino acid is not indispensable in maintaining more or less the biological activities of ANG II molecule.

A 23-yr-old male patient with normotensive primary aldosteronism is reported. He complained of muscle weakness, polydipsia, and polyuria. His blood pressure was generally 118/60 to 124/70 mm Hg. Serum sodium, potassium and chloride were 152.2.2, and 108 meq/liter, respectively. Arterial blood pH, glomerular filtration rate, renal plasma flow and circulating plasma and blood volumes were normal, and plasma bicarbonate was normal or elevated. PRA was 0.16 ng/ml.h and did not increase significantly after sodium deprivation, ambulation, and iv furosemide injection. Plasma aldosterone was 64.1 ng/100 ml. He showed pressor responses to infused angiotensin II and norepinephrine which were similar to those in normal men. Adrenal scintiscanning after iv injection of [131I]6 beta-iodomethyl-19-nor-cholesterol during dexamethasone administration showed dense uptake on the right adrenal and minimal uptake on the left. Intravenous infusion of angiotensin III at a rate of 20 ng/kg. min for 30 min did not cause an increase in plasma aldosterone. Serum electrolytes became normal after spironolactone but not after dexamethasone. At surgery, the right adrenal, bearing a benign adenoma, was removed. After surgery, blood pressure was unchanged, but all biochemical abnormalities disappeared. The cause of this normotension remains to be elucidated, but the diagnosis criteria of primary aldosteronism should now be partly modified.

Preliminary design studies on high conversion pressurized water reactors (HCPWRs) have been completed, and plant design studies are currently being performed to improve the feasibility of HCPWRs. The present status of the feasibility studies is covered, and the related validation tests to be conducted in the coming years are reviewed.

Relative lipolytic activity of human parathyroid hormone-(1-34) (hPTH-(1-34], hPTH-(3-34), desamino-Ser1-hPTH-(1-34), and rat PTH-(1-34) was compared in human subcutaneous adipose tissues in vitro. Human PTH-(1-34), rat PTH-(1-34), and desamino-Ser1-hPTH-(1-34) stimulated in vitro lipolysis significantly above basal level at the concentration of 10(-6) M. Average increments of lipolytic rate were 2.39, 1.82, and 0.87 mumol/g per 2 hr, respectively, being significantly different among the three groups. On the other hand, hPTH-(3-34)-induced lipolytic rate was 0.83 +/- 0.18 mumol/g per 2 hr, not significantly different from the basal level (0.71 +/- 0.20 mumol/g per 2 hr). The effect of hPTH-(3-34) on glycerol release stimulated by hPTH-(1-34), isoproterenol, or forskolin was subsequently investigated. Human PTH-(3-34) produced a dose-dependent inhibition of hPTH-(1-34)-stimulated lipolysis. In contrast, isoproterenol- and forskolin-induced lipolytic rates were not influenced by hPTH-(3-34). The effect of propranolol on hPTH-(1-34)- or isoproterenol-induced lipolysis was also studied. Propranolol dose-dependently inhibited isoproterenol-induced lipolysis but had no effect on lipolysis stimulated by hPTH-(1-34). These results suggest that the amino acids at positions 1 (serine) and 2 (valine) of PTH are critical for the stimulation of lipolysis in human adipose tissue. Human PTH-(1-34) causes lipolysis after binding to receptors distinct from beta-adrenergic receptors of fat cells and possibly hPTH-(3-34) inhibits hPTH-(1-34)-stimulated lipolysis by competing at the level of PTH receptor.

The effect of diltiazem hydrochloride (DTZ), a calcium-antagonist, on pressor and steroidogenic action of angiotensin II (AII), angiotensin III (AIII) and norepinephrine (NE) was studied in 5 normal men. AII, AIII and NE were infused intravenously for 50 min from 0900 hr at a rate of 20 ng/kg/min, 100 ng/kg/min and 200 ng/kg/min, respectively. DTZ was infused intravenously alone or in combination with each of these pressor substances at a rate of 1 mg/min from 0910 hr to 0930 hr. DTZ alone did not cause significant changes in blood pressure (BP) and plasma aldosterone concentration (P1 Aldo). On the other hand, DTZ combined with AII, AIII or NE significantly inhibited the rise in BP induced by these pressor substances. DTZ also inhibited the NE-induced increase in P1 Aldo, whereas it did dot alter AII-, or AIII-induced increase in P1 Aldo. These results indicate that in normal men pressor actions of AII, AIII and NE are calcium-dependent and calcium ions are also involved in NE-induced increase in P1 Aldo.

In 5 normal men an intravenous injection of 0.5 mg of synthetic 1-24 ACTH caused a significant increase in plasma aldosterone and a simultaneous intravenous infusion of 600 ng/kg/min of des-asp1-, ileu8-angiotensin II (AIIIA) did not inhibit this increase. Since this dose of AIIIA is known to inhibit an angiotensin II-induced increase in plasma aldosterone in normal men, the present results suggest that the ACTH-induced aldosterone stimulation is mediated by an adrenocortical receptor which is different from angiotensin II receptors.

The biololgical activity of des-asp1-,des-arg2-angiotensin II (3-8AII) was studied in man. When 3-8AII was infused iv at rates of 22 and 308 pmol (17.5 and 250 ng)/kg · min separately into 5 normal men each for 120 min, blood pressure showed no change, plasma renin activity (PRA) decreased gradually and plasma aldosterone showed a gradual slight increase. The lower dose of 3-8AII partially inhibited captopril-induced PRA increase and plasma aldosterone decrease in the same 5 normal men and the higher dose of the hexapeptide completely abolished them. In one of the 5 normal men blood pressure rose in response to doses of 3-8AII greater than 2220 pmol (1750 ng)/kg · min. When 3-8AII was infused iv at 308 pmol/kg · min into 2 patients with Bartter's syndrome for 60 min, it caused marked decreases in PRA and plasma aldosterone but no change in blood pressure. This decrease in plasma aldosterone is thought to be secondary to the decrease in PRA. From these results it is evident that 3-8AII has a minimal pressor action, a weak aldosterone-stimulating action and a significant renin-suppressing action in man and this PRA-lowering action is thought to be due to direct inhibition of renin release by its whole molecule or a smaller part of the molecule.

Following a simultaneous intravenous injection of dehydroepiandrosterone 35S-sulphate (DHA-35S) and 3H-dehydroepiandrosterone sulphate (3H-DHA-S) into normal subjects, patients with liver cirrhosis (LC) and patients with acute hepatitis (AH), disappearance curves of 3H-DHA-S and of DHA-35S over 36 hours were calculated for each individual subject. The three groups were compared with regard to the following parameters: slope of DHA-35S and 3H-DHA-S and ratio of the slope of DHA-35S to that of 3H-DHA-S (S/H) in the initial part and in the later part of each exponential curve; metabolic clearance rates (MCR), distribution volumes and transfer rates. The initial slope of DHA-35S of the control group was not significantly different from that of the AH group, but the initial slope of both groups was lower than that of the LC group. The initial slope of 3H-DHA-S of the control group was lower than that of the other two slopes which were not significantly different from each other. The S/H ratio (an indicator of sulphokinase activity) of the control group was significantly higher than that of the other two groups and the ratio of the LC group was higher than that of the AH group. The transfer rate between the inner and outer pool was greater in both the patient groups than in the normal subjects. There was no difference in MCR's and distribution volumes among the three groups. The results suggest a decreased activity of sulphokinase in the liver of patients with both liver cirrhosis and acute hepatitis; its activity in the latter case being more impaired than in the former case. The sulphatase activity may also be damaged to the same extent.

In 5 normal men intravenous infusion of 600 ng/kg/min of des-asp1-,ileu8-angiotensin II (AIIIA) inhibited a rise in blood pressure as well as increase in plasma aldosterone caused by an intravenous infusion of 20 or 100 ng/kg/min of des-asp1-angiotensin II (angiotensin III, AIII). This result and our previous study on simultaneous infusions of 600 ng/kg/min of AIIIA and 20 ng/kg/min of angiotensin II (All) in the same 5 normal men demonstrate that this dose of AIIIA antagonizes AIII and All on the adrenal cortex as well as peripheral arterioles and that AIIIA has the same degree of inhibitory effect on the aldosterone-stimulating action of AIII and on that of All in man.

Studies have been made on the extraction of iodinated compounds from human serum, their chromatographic separation on filter paper, and their detection by a eerie sulfate-arsenious acid reagent, followed by staining with aniline in acetone and neutralizing with sodium bicarbonate. Chloride simulated iodine compounds on chromatograms. Thiouracil, thiouracil disulfide and propylthiouracil were found to reduce eerie ion catalytically and when run in certain solvent systems moved to positions which could cause confusion with the iodotyrosines or iodothyronines. Only thyroxine and iodide were regularly identified in normal human serum, but small amounts of unknown positive- reacting compounds were found among patients with simple goiter.

Pressor activity and speed of metabolic degradation of angiotensin II-(2-7)-hexapeptide [ANG-(2-7)] were studied in 5 normal men. When infused iv at a rate of 72 nmol/kg X min for 7 min, ANG-(2-7) caused a very slight but statistically significant increase in blood pressure. Average blood pressure increases at 2, 5 and 7 min were 5/4, 8/10 and 8/9 mmHg, respectively, and the duration of the pressor action after the cessation of the infusion (T) was 5 min on the average. The pressor activity and T of this peptide were much less than or shorter than those of angiotensin II-(1-7)-heptapeptide [ANG-(1-7)] infused previously in the same 5 normal men at a rate of 18 nmol/kg X min, indicating that the pressor activity ratio of both the peptides in man is 1: greater than 7.2 which is similar to that of angiotensin II-(2-8)-heptapeptide (angiotensin III) and Ile5-angiotensin II (Ile5-ANG II) (1: greater than 5) and that the removal of N-terminal aspartic acid from ANG-(1-7) hastens the speed of metabolic degradation of the peptide as from Ile5-ANG II.

1. When the angiotensin II-(4-8)-pentapeptide was infused intravenously at rates of 0.31-5.55 nmol min−1 kg−1 for 10–120 min into five normal men or two patients with Bartter's syndrome, no significant change was observed in blood pressure, plasma renin activity and plasma aldosterone, and the lowest dose did not inhibit the captopril-induced increase in plasma renin activity in the normal men. 2. An intravenous infusion of the pentapeptide at 9–0 nmol min−1 kg−1 for 15 min significantly raised blood pressure in the five normal men but not in patients with Bartter's syndrome. Blood pressure returned to the pre-treatment level 60 min after the cessation of the infusion in the normal men. 3. At the same dose level none of the seven subjects examined showed any significant change in plasma renin activity and plasma aldosterone. 4. Angiotensin II-(5-8)-tetrapeptide was infused intravenously into one of the normal men at a rate of 41.5 nmol min−1 kg−1 for 15 min, but it caused no significant change in blood pressure, plasma renin activity and plasma aldosterone. 5. These results suggest that the pentapeptide and probably the tetrapeptide do not possess renin-suppressing and steroidogenic actions in man but that the former peptide does elicit a modest pressor action with a prolonged duration.

Described here is a 21-year-old man, who had several episodes of generalized muscle weakness, blepharoptosis and a diffuse goiter. The results of thyroid function tests and histological findings of specimen obtained by thyroid biopsy was compatible with mild Graves' disease. Blepharoptosis was moderately improved immediately after edrophonium injection, thus established the diagnosis of occular type of myasthenia gravis. In addition, the patient had markedly diminished serum potassium level, in association with markedly elevated plasma renin activity (PRA). Plasma aldosterone concentration (PAC) and urinary aldosterone excretion (UAE) were also moderately increased. The insensitivity to pressor effect of infused synthetic angiotensin II and hyperplasia of the juxtaglomerular apparatus of the kidney in histological examination substantiated the diagnosis of Bartter's syndrome complicated with Graves' disease and myasthenia gravis.In order to investigate the effect of indomethacin, an inhibitor of prostaglandin biosynthesis, on the biochemical abnormalities of Bartter's syndrome, indomethacin (75mg/day) was given with spironolactone and potassium treatment. However, the biochemical abnormalities were not corrected and, moreover, muscle weakness and further decrease in potassium level were observed during the treatment with indomethacin alone. The findings suggest that the abnormalities observed in this patient could not be explained by the overproduction of renal prostaglandin.The present case with Bartter's syndrome was characterized by complicating of Graves' disease and myasthenia gravis, both of which have been regarded as autoimmune diseases. Immunological studies, including subpopulation of lymphocyte determined by surface immunoglobulin bearing cells, rosette formation and blastoid formation, revealed the suppression of B lymphocyte population in the present case. Although these immunological abnormalities were corrected after administration of azathioprine, an immunosuppressive agent, serum potassium level was not ameliorated. The result suggest that immunological mechanism is not related to the etiology of Bartter's syndrome in the present case.

Studies were conducted to determine whether or not angiotensin III [AIII] and angiotensin II-(3-8)-hexapeptide [ANG-(3–8)] have their own specific arteriolar binding sites different from angiotensin II [AII] binding site(s) in man. Four patients with Bartter's syndrome were given asn1-,val5-AII by iv infusion at rates of 10, 20, 50 and 100 pmol/kg · min, each for 7 min. One hour later AIII was infused iv in the same 4 patients at rates of 50, 100, 250 and 500 pmol/kg · min, each for 7 min. After 100 or 150 mg/day of indomethacin treatment for 7 days, the same All and AIII infusions were repeated. All patients showed blunted pressor responses to both All and AIII before indomethacin and the responses were improved after indomethacin. Moreover, increment curves of blood pressure for AII were almost identical with those for AIII in individual patients both before and after indomethacin. ANG-(3–8) was infused iv in 3 normal men and 3 of the 4 patients with Bartter's syndrome at a rate of 3.500 pmol (2.838 ng)/kg·min for 15 min. Blood pressure rose in the normal men (12/12 mmHg on the average) but did not rise in the patients. These results suggest that All, AIII and ANG-(3–8) have the same arteriolar binding sites in man.

One hundred milligrams of oral captopril (SQ 14225) caused a significant increase in PRA and a significant decrease in plasma aldosterone (PA) in five normal men and five hypertensive patients. Blood pressure (BP) showed no change in the normal men, but it fell significantly in the patients. An iv infusion of 200 ng/kg.min des-Asp1-,Ileu8-angiotensin II (AIIIA) for 2 h caused a significant decrease in PRA and a slight but significant increase in PA, but caused no change in BP in the normal men. When 100 mg captopril were given orally immediately before the start of the AIIIA infusion, BP showed no change in the normal men, but fell in the patients. However, PRA showed a significant decrease and PA showed a slight but significant increase in both the normal men and the patients, except for one patient with renovascular hypertension who showed a decrease in PA. Thus, this suppression of captopril-induced PRA increase by AIIIA, a derivative of angiotensin II, is not related to BP change, and it suggests that the principal cause of the PRA increase after captopril is a disappearance of endogenous angiotensin II.

Effects of an orally active angiotensin I-converting enzyme inhibitor, SQ 14225, on the actions of angiotensin I (AI) infused intravenously for 120 to 390 min were studied in 5 normal men. When 20 ng/kg/min of AI infusion was started immediately after a single oral administration of 100 mg of SQ 14225, a significant rise in blood pressure (BP) was observed for the first 15 min, but BP began to fall from 17 min and returned to the pretreatment level at 45 min. This BP level continued at least to 120 min and in one subject to 180 min. In this subject BP began to rise again from 185 min and reached the level of 15 min at 390 min. Plasma AI level increased gradually from 45 min. At 15 min plasma renin activity (PRA) decreased and plasma aldosterone (PA) increased, but then PRA began to increase and PA began to decrease. At 120 min the values of PRA and PA were similar to the pretreatment values. In one subject plasma AI and PRA began to decrease and PA began to increase after 120 or 180 min. On the other hand, in the 5 men sole AI infusion caused a continued BP rise, PRA decrease and PA increase, and sole SQ 14225 administration caused increases in plasma AI and PRA and a decrease in PA but no BP change. From these results it was concluded that complete blockade and partial inhibition of AI conversion by 100 mg of oral SQ 14225 lasted for about 2.5 and 6.5 hr, respectively and that BP rise, PRA suppression and aldosterone stimulation after AI infusion were entirely due to the actions of angiotensin II converted from AI.

SUMMARY 1. Changes in plasma active and inactive renin concentration (ARC and IRC) after captopril administration and angiotensin II (AII) infusion were studied in six patients with Bartter's syndrome. 2. A single oral dose of captopril (8-25 mg) lowered the blood pressure and increased both ARC and IRC. AII infusion elevated blood pressure, suppressed ARC and increased IRC. 3. In this syndrome of high renin levels, infused AII appeared to increase inactive renin secretion by reducing its conversion to active renin. On the other hand, an acute fall in AII levels and/or renal perfusion pressure by captopril increased both active and inactive renin. This indicates that the increase in the secretion of inactive renin, stimulated by captopril, might exceed any increase in its conversion to active renin in patients with Bartter's syndrome, in whom the production of renin is accelerated, and conversion of inactive renin to active renin probably already operates near its maximum.

In order to examine whether substrate specificity of angiotensin-converting enzyme (ACE) exists or not for N-terminal substituted angiotensin I (ANG I) in man, biological activities of sarcosine1-angiotensin I (Sar1-ANG I) and the effects of an ACE inhibitor, captopril, on the Sar1-ANG I activities were studied in 5 normal men. The following 3 experiments were done at 1 week intervals. Sarcosine1-angiotensin II (Sar1-ANG II) was infused iv at a rate of 5 pmol/kg X min from 0900 h to 0930 h in 5 normal men in a recumbent position. Blood pressure rose remarkably and the average increment was 38/31 mmHg at 30 min (p less than 0.001). Average duration of the pressor action after the cessation of the infusion (T) was 40 min for systolic and 50 min for diastolic and much longer than T of isoleucine5-angiotensin II. Plasma renin activity (PRA) decreased (p less than 0.01) and plasma aldosterone (PA) increased significantly (p less than 0.01). Sar1-ANG I was infused iv at a rate of 5 pmol/kg X min from 0900 h to 0930 h. Blood pressure rose to the same extent as in (1) (p less than 0.001). T was 40 min for both systolic and diastolic and much longer than T of ANG I in man. PRA decreased (p less than 0.01) and PA increased (p less than 0.01) significantly. Oral 100 mg captopril was given at 08:00 h and Sar1-ANG I was infused iv at a rate of 5 pmol/kg X min from 09:00 h to 09:30 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological activities of asn1-,val5-angiotensin II (Hypertensin, Ciba, Asn1-,Val5-ANG II), ile5-angiotensin II (human angiotensin II, Ile5-ANG II) and sar1-angiotensin II (Sar1-ANG II) were compared in man. In 7 normal men 5 pmol/kg X min each of Asn1-,Val5-ANG II, Ile5-ANG II and Sar1-ANG II was infused iv from 0900 h to 0930 h at 1-week intervals. Average increments of blood pressure at the end of the infusions were 11/12, 23/20 and 36/30 mmHg, respectively (significant differences among the 3: P less than 0.001), average decrements of plasma renin activity were 0.30, 0.32 and 0.27 ng/ml X H, respectively (no significant difference among the 3), average increments of plasma aldosterone were 1.1, 2.3 and 4.4 ng/100 ml, respectively (significant difference between the former 2: P les than 0.001, between the latter 2: P less than 0.02), and durations of blood pressure rise after the cessation of these infusions (T) were 2-5 (average 5) min, 10-25 (average 20) min and 35-60 (average 40) min, respectively (significant difference between the former 2:less than P 0.01, between the latter 2: P less than 0.001). From these results it is evident that the pressor and steroidogenic actions of Ile5-ANG II are significantly stronger than those of Asn1-,Val5-ANG II and that the duration of pressor action of the former is much longer than that of the latter. Therefore, when the activities of angiotensin II (ANG II) derivatives are compared with those of ANG II in man, Ile5-ANG II--natural human ANG II--should always be used instead of Asn1-,Val5-ANG II. The pressor and steroidogenic actions and T of Sar1-ANG II are significantly stronger or longer than those of Ile5-ANG II. The reason for this is thought to be that Sar1-ANG II is bound tightly to the vascular and adrenal ANG II receptors and is not readily metabolized.

We report a case of a prolactin-secreting pituitary tumor in a man whose characteristic findings were ejaculatory incompetence and no response of gonadotropin to clomiphene. After treatment with bromocriptine ejaculation was normal, gonadotropin responded slightly to clomiphene and the high level of plasma prolactin returned to normal. A Hardy operation was performed to remove the pituitary tumor. The patient continues to receive 2.5 mg. bromocriptine daily to maintain normal ejaculation.