In situ demonstration of angiotensin-dependent and independent pathways for hyperaldosteronism during chronic extracellular fluid volume depletion.

In wild-type mice, 2-wk administration of losartan, an angiotensin (Ang) II type 1 (AT1) receptor antagonist, along with dietary sodium restriction, resulted in an elevation of plasma aldosterone greater than that seen with sodium restriction alone (2.75 +/- 0.35 vs. 1.38 +/- 0.16 ng/ml, P < 0.01). Plasma potassium increased in sodium-restricted, losartan-treated mice (6.0 +/- 0.2 mEq/liter), while potassium remained unchanged in mice with sodium restriction alone. To study the effect of Ang II on glomerulosa cells that may operate independently of plasma potassium in situ, we used chimeric mice made of cells with or without the intact AT1A gene (Agtr1a). When animals were fed a normal diet or chronically infused with Ang II, the aldosterone synthase mRNA was detectable only in Agtr1a+/+ but not Agtr1a-/- zona glomerulosa cells. After 2 wk of sodium restriction, plasma aldosterone increased (1.51 +/- 0.27 ng/ml) and potassium remained on average at 4.5 +/- 0.2 mEq/liter, with aldosterone synthase mRNA expressed intensively in Agtr1a+/+, but not detectable in Agtr1a-/- cells. Simultaneous sodium restriction and losartan treatment caused increases in plasma potassium (5.5 +/- 0.1 mEq/liter) and aldosterone (1.84 +/- 0.38 ng/ml), with both Agtr1a-/- and Agtr1a+/+ cells intensively expressing aldosterone synthase mRNA. Thus, aldosterone production is regulated by Ang II in the adrenal gland during chronic alterations in extracellular fluid volume when plasma potassium is maintained within the normal range. In the light of a previous observation that dietary potassium restriction superimposed on sodium restriction abolished secondary hyperaldosteronism in angiotensinogen null-mutant mice, the present findings demonstrate that when the renin-Ang system is compromised, plasma potassium acts as an effective alternative mechanism for the volume homeostasis through its capacity to induce hyperaldosteronism.

Scc1/Rad21/Mcd1 is required for sister chromatid cohesion and kinetochore function in vertebrate cells.

Proteolytic cleavage of the cohesin subunit Scc1 is a consistent feature of anaphase onset, although temporal differences exist between eukaryotes in cohesin loss from chromosome arms, as distinct from centromeres. We describe the effects of genetic deletion of Scc1 in chicken DT40 cells. Scc1 loss caused premature sister chromatid separation but did not disrupt chromosome condensation. Scc1 mutants showed defective repair of spontaneous and induced DNA damage. Scc1-deficient cells frequently failed to complete metaphase chromosome alignment and showed chromosome segregation defects, suggesting aberrant kinetochore function. Notably, the chromosome passenger INCENP did not localize normally to centromeres, while the constitutive kinetochore proteins CENP-C and CENP-H behaved normally. These results suggest a role for Scc1 in mitotic regulation, along with cohesion.

[Treatment outcomes with vinorelbine for metastatic breast cancer patients previously treated with both doxorubicin and docetaxel].

The purpose of this study was to evaluate the efficacy and toxicity of weekly vinorelbine (VNB) in patients with metastatic breast cancer previously treated with both adriamycin (ADM) and docetaxel (TXT). VNB was administered weekly at the dose 20 mg/m2 by i.v. infusion over 20 minutes followed by flushing the vein with 100 ml of normal saline. From June 1999 to August 2000, ten patients were enrolled in this study. Patient characteristics were that the cumulative doses (median) of previous ADM and TXT were 300 mg (range, 120-880 mg), 560 mg (range, 120-960 mg) respectively. The median number of metastatic sites was four, with poor performance status (ECOG 1-2: 40%, 3-4: 60%). The median cycles of weekly VNB were seven (range: 2-12). Two of 10 assessable patients obtained partial response, with an overall response rate of 20%. The main toxicity (NCI grade 4) was leukopenia in 10% of 10 patients. Phlebitis (grade 2) was observed in 4 of 10 patients (40%). VNB is an active agent against metastatic breast cancer pretreated with both ADM and TXT, possessing no severe toxicities.

The nutritional advantages of proximal gastrectomy for early gastric cancer.

BACKGROUND/AIMS: Total gastrectomy has generally been performed for the treatment of early gastric cancers involving the upper third of the stomach. However, proximal gastrectomy has also been used for the treatment of cardial early gastric cancer. METHODOLOGY: To compare the nutritional parameters after proximal gastrectomy with the parameters after total gastrectomy, and to also determine the advantages of the postoperative nutritional states, a retrospective analysis was made to evaluate the nutritional status of patients with early gastric cancer who underwent proximal gastrectomy with those undergoing total gastrectomy. Forty-nine patients were studied for one year after surgery; 9 underwent proximal gastrectomy while 40 had a total gastrectomy. RESULTS: Proximal gastrectomy allowed the patient to better maintain both their nutritional parameters and body weight. CONCLUSIONS: Proximal gastrectomy was thus found to be a beneficial modality for early gastric cancer patients regarding terms of the postoperative nutritional status, in comparison to total gastrectomy.

Bir1/Cut17 moving from chromosome to spindle upon the loss of cohesion is required for condensation, spindle elongation and repair.

BACKGROUND: In mammals, proteins containing BIR domains (IAPs and survivin) are implicated in inhibiting apoptosis and sister chromatid separation. In the nematode, Bir1 is required for a proper localization of aurora kinase, which moves from the mitotic chromosome in metaphase to the spindle midzone in anaphase as a passenger. Fission yeast Bir1/Pbh1 is essential for normal mitosis. RESULTS: A temperature sensitive mutant cut17-275 exhibits the defect in condensation and spindle elongation at 36 degrees C, while securin is degraded. Gene cloning shows that the cut17+ gene is identical to bir1+/pbh1+. At 26 degrees C, cut17-275 is UV sensitive as the repair of DNA damage is severely compromised. Bir1/Cut17 is a nuclear protein in interphase, which is then required for recruiting condensin to the mitotic nucleus, and concentrates to form a discrete number of dots from prometaphase to metaphase. Once the chromatids are separated, Bir1/Cut17 no longer binds to kinetochores and instead moves to the middle of spindle. Chromatin immunoprecipitation suggested that Bir1/Cut17 associates with the outer repetitious centromere region in metaphase. Following the initiation of anaphase the protein switches from being a chromosomal protein to a spindle protein. This transit is stringently regulated by the state of sister chromatid cohesion proteins Mis4 and Rad21. Ark1, is an aurora kinase homologue whose mitotic distribution is identical to, and under the control of Bir1/Cut17. CONCLUSIONS: Bir1/Cut17 and Ark1 act as "passengers" but they may play a main role as a recruitment factor, essential for condensation, spindle elongation and DNA repair. Bir1/Cut17 should have roles both in mitotic and in interphase chromosome. The proper location of Ark1 requires Bir1/Cut17, and the mitotic localization of Bir1/Cut17 requires sister cohesion.

EXAFS measurements for liquid Ge-Si alloys.

EXAFS measurements around the Ge-K edge have been carried out for liquid Ge-Si alloys for the first time to investigate the local structure around a Ge atom. To perform the EXAFS measurements for the liquid alloys with high melting temperatures, a new sapphire cell have been developed. The measurements were carried out for the liquid alloys from 10% to 60% of Si and the crystalline ones from 10% to 70% of Si as a reference. EXAFS oscillations, x(k), are observed even at 1480 degrees C for liquid Ge(0.4)Si(0.6). The position of the first peak in the radial distribution function obtained from Fourier transform of x(k) is shifted towards smaller distance for liquid and crystalline alloys with increasing Si concentration. The results of a curve-fit analysis in a harmonic approximation show that Ge-Ge and Ge-Si bonds in the liquid alloys become long with increasing Si concentration while those become slightly short in the crystaline ones.

Direct hypogastric artery reconstruction for threatened lower limb ischemia: report of a case.

The hypogastric artery is one of the major collateral arteries in aortoiliac occlusive disease. This report describes a case of limb-threatening ischemia caused by acute arterial thrombosis of the right hypogastric artery. The external iliac and distal arteries were obstructed and the hypogastric artery was a major collateral artery. A diagnostic arteriogram taken after intra-arterial thrombolytic therapy revealed a stenotic lesion in the orifice of the hypogastric artery. Open thromboendarterectomy of the hypogastric artery and patch angioplasty, using an expanded polytetrafluoroethylene graft, were performed to salvage the limb. The hypogastric artery was successfully revascularized and ischemic rest pain was relieved.

Production and use of chimeric mice.

The gene-targeting technology allows complete and selective inactivation of a specific gene to study the consequence of total absence of the gene product. The availability of such null-mutant mice enables investigators to identify the biological function of the gene product in physiological or pathophysiological conditions. This technology, popularly known as "gene knockout," can also induce more subtle mutations at the targeted site of the genome.

Clinicopathological features of long-term survivors of scirrhous gastric cancer.

BACKGROUND/AIMS: Prognosis of scirrhous gastric cancer remains low. To determine the clinicopathological features that are correlated with prognosis, we studied long-term survivors of scirrhous gastric cancer (survival duration more than 5 years) in comparison with patients with short survival. METHODOLOGY: Among 2719 gastric cancer patients who underwent surgery at Matsuyama Red Cross Hospital, 211 cases were diagnosed as scirrhous type gastric cancer. Seventeen patients survived more than 5 years, and the rest had short survival (less than 5 years). Comparison of clinicopathological factors was done by chi 2 analysis. Multivariate analysis was done in order to focus on the prognostic factors. RESULTS: The 5-year survival of the total 211 patients was 12%. The 5-year survival of patients who underwent curative surgery (67 cases) was 30%, which was significantly higher than that of the non-curative surgery group (144 cases, 6%). Significant differences were noted in the following variables: peritoneal dissemination, hepatic metastasis, lymph node dissection, pattern of infiltrating growth, depth of invasion, histological lymph node metastasis, histological stage, and histological curability. Patients with either hepatic metastasis or peritoneal dissemination did not survive 5 years. Multivariate analysis revealed that the most significant independent prognostic factor was histological curability, followed by peritoneal dissemination. CONCLUSIONS: There is a possibility of long-term survival for patients with scirrhous gastric cancers without hepatic metastasis, peritoneal dissemination, or extensive lymph node metastasis. Curative surgery is important, suggesting that the extended operation is rational if possible.

Salutary role for angiotensin in partial urinary tract obstruction.

BACKGROUND: In the neonatal period, angiotensin II (Ang II) is up-regulated and induces a timely development of the renal pelvis and ureteral peristalsis, thereby protecting the kidney from hydronephrosis. We tested the possibility that in adulthood, Ang II may act salutarily on the kidney structure during partial urinary tract obstruction by inducing adaptive changes in the peristaltic machinery. METHODS: Adult male Sprague-Dawley rats were subjected to partial unilateral ureteral obstruction (UUO) and divided into two groups, that is, those treated with (group L, N = 21) and those without (group C, N = 21) an angiotensin type 1 (AT1) receptor antagonist (losartan). Control animals were sham operated (N = 10). Rats were sacrificed either at day 7 or day 14. RESULTS: The degree of hydronephrosis determined morphometrically was significantly more severe in group L than group C at both day 7 and day 14, indicating that Ang II inhibition accentuated hydronephrosis. The measurement of upstream pressure within the partially ligated ureter in vivo revealed that losartan significantly attenuates the frequency of ureteral peristaltic activities. In in vitro studies using ureteral strips harvested from normal adult Sprague-Dawley rats (N = 10), Ang II (10(-8) mol/L) was shown to augment contraction, which was completely inhibited by losartan (10(-6) mol/L). CONCLUSIONS: Ang II has a salutary effect of protecting kidneys from hydronephrosis during partial ureteral obstruction through its ability to augment ureteral peristalsis.

Superior mesenteric vein thrombosis due to diverticulitis and spontaneous thrombolysis after ilio-cecal resection. A case report.

Inflammation or infection is one of the major causes of superior mesenteric vein thrombosis. A case of secondary superior mesenteric vein thrombosis is presented, which was identified with enhanced CT. The mesenteric venous thrombosis was due to diverticulitis of the ileum, and ilio-cecal resection was performed. Because no findings of intestinal ischemia were present, thrombectomy was not attempted. After surgery, the patient was followed up by repeated CT scan, and spontaneous thrombolysis without thrombectomy or thrombolytic therapy was exhibited. The present case indicated abdominal inflammation or infection strongly related to the development and regression of mesenteric venous thrombosis.

[Efficacy of UFT in the treatment of para-aortic lymph node metastasis following gastric cancer surgery: case report].

The patient was a 68-year-old man who underwent pyloric gastrectomy for advanced stomach cancer on December 6, 1996. The histopathological diagnosis was poorly differentiated adenocarcinoma, ss, ly3, v1, n2 (+), and stage IIIa. Postoperative adjuvant chemotherapy consisted of short-term intravenous infusion of 5-FU, 320 mg/m2/day (= 480 mg/body) for 5 days beginning on postoperative day (POD) 1, and oral 5-FU, 200 mg/day, for 1 year beginning on POD 14. The preoperative CEA value was 316.2 ng, but it fluctuated below 10 ng postoperatively. About one year after the operation, the patient began to complain of epigastric pain, loss of appetite, and general malaise. CT of the upper abdomen revealed a 1.5-cm para-aortic lymph node, and the CEA value of 319.0 ng was abnormally high. 5-FU was stopped, oral UFT at 300 mg/day was started, and the patient's course was followed. Three months after the start of UFT, the lymph node had shrunk on CT (shrinkage rate: 66.7%), and the CEA value had decreased to 14.3 ng. As though corresponding to these changes there was a gradual decrease in the epigastric pain, general malaise, etc., and the patient's appetite also returned. There were no subsequent elevations in the CEA values or increases in the size of the para-aortic lymph nodes, and the patient's general condition was favorably maintained. UFT appeared to be effective against the lymph node metastasis around the aorta in this case.

Dual renin gene targeting by Cre-mediated interchromosomal recombination.

This study describes a new approach to targeting clustered genes. Our study began with the establishment of two lines of mice carrying different mutations in either Ren1 or Ren2. These two genes, both encoding renin, span over 40 kb in tandem on chromosome 1. Each gene was mutated by gene targeting to contain loxP sites. These two mutants and Cre transgenic mice were mated to produce offspring carrying the mutant Ren1 and Ren2 genes, as well as the Cre transgene concurrently. Initially, two mutant Ren genes were located on separate chromosomes. Southern analysis of mice from the second generation revealed that the mutant Ren1 and Ren2 were interchromosomally recombined at the loxP sites to produce a new dually mutated allele on the chromosome at the rate of 9.6% (7/73). Thus, interchromosomal recombination can be efficiently programmed by mating as designed using the Cre-loxP system.

Effect of inhaled nitric oxide on cardiovascular response to catecholamine in heart failure.

We examined the dose responses to continuous infusion of isoproterenol (ISO) and norepinephrine (NE) in normal (control) and procainamide-induced heart failure dogs with or without inhalation of 70 ppm nitric oxide (NO). Inhaled NO affected neither left ventricular (LV) function nor hemodynamics at baseline in both control and heart failure dogs. There were no significant differences in the responses to ISO and NE with or without inhaled NO in the control. The responses of LV dP/dt to ISO and NE were significantly enhanced in heart failure; however, they were not affected by inhaled NO. In contrast, LV pressure and dimension at end diastole were significantly increased, and pulmonary vascular resistance (PVR) was significantly decreased by inhaled NO during infusion of both ISO and NE in heart failure. In conclusion, the positive inotropic response to cathecholamine is not affected by inhaled NO even in heart failure. Inhaled NO decreases PVR, but potentially increases LV preload in the presence of additional stress of cathecholamine in heart failure.

Laparoscopic splenectomy using a wall-lifting procedure.

A laparoscopic splenectomy using a hanger wall-lifting procedure is herein described. The patient is placed in the right lateral position. The left lower chest and left abdominal wall are then lifted by three wires in two directions, left laterally and vertical to the abdominal wall. The view of the operative field thus obtained is excellent. The lifting wires and bars do not hinder the movement of the forceps, since the angles of the instruments to approach the spleen are different from those of the wires. A laparoscopic splenectomy using this wall-lifting procedure avoids the usual complications associated with pneumoperitoneum while still being technically comparable to a procedure with pneumoperitoneum.

Pre-operative imaging can diagnose torsion of the gallbladder: report of a case.

Torsion of the gallbladder is a rare disease and pre-operative diagnosis of the disease is uncommon. About 400 cases have been reported, but only 4 were diagnosed by pre-operative imaging. We report on a case of gallbladder volvulus diagnosed pre-operatively using pre-operative imaging with ultrasound and computed tomography.

Potent antihypertrophic effect of the bradykinin B2 receptor system on the renal vasculature.

BACKGROUND: Angiotensin type 1 (AT1) receptor-deficient mice (Agtr1-/-), which selectively lack both AT1A and AT1B receptor genes, are characterized by marked intrarenal vascular thickening. In the present study, we explored the possible involvement of the kinin-kallikrein system in the development of this renal vascular hypertrophy. METHODS: Wild-type and Agtr1-/- mice were examined for the developmental regulation pattern of the kinin-kallikrein system and treated with aprotinin (a kallikrein inhibitor), AcLys [D-b Nal7, Ile8] des-Arg9-bradykinin (a bradykinin B1 receptor antagonist), or Hoe-140 (a bradykinin B2 receptor antagonist) from 3 to 14 days of age. RESULTS: The normal postnatal up-regulation of kininase II was organ-specifically suppressed in Agtr1-/- kidneys at 2 and 3 weeks of age. Immunohistochemical staining in Agtr1-/- mice revealed tissue kallikrein staining along the nephron from connecting tubules to cortical collecting tubules in proximity to the hypertrophic vasculature, whereas tissue kallikrein staining was confined to connecting tubules in wild-type mice. Aprotinin and Hoe-140 accelerated the vascular hypertrophy significantly as determined by wall thickness ratio, whereas B1 receptor antagonism had no effect. CONCLUSION: The kinin-kallikrein system in the Agtr1-/- mouse kidney is functionally activated by local suppression of kininase II and extensive redistribution of kallikrein to perivascular areas. This activation, specific to the kidney, serves to dampen a development of the marked vascular hypertrophy. These results demonstrate, to our knowledge for the first time, the antihypertrophic effect of the bradykinin B2 receptor system on the renal vasculature in vivo.

[Effects of DAC (doxifluridine, adriamycin, cyclophosphamide) chemotherapy in advanced breast cancer patients].

Effects of DAC (doxifluridine (5'-DFUR), adriamycin (ADM), cyclophosphamide (CPA)) chemotherapy were evaluated in seven patients with advanced breast cancer. 5'-DFUR of 600 mg was orally daily, ADM of 40 mg/m2 was administered intravenously (bolus) at day 1 and CPA of 400 mg/m2 was administered intravenously (one shot) at day 1 and day 8. These were repeated as one cycle of 21 days. Two complete responses, three partial responses and two progressive diseases were obtained, and the response rate was 71% (95% confidence interval: 29-96%). The side-effects of more than grade 3 were observed in leucocytopenia (4/7), neutrocytopenia (6/7), anorexia (2/7), nausea or vomiting (2/7) and alopecia (6/7). These results suggest that DAC chemotherapy is a novel, attractive regimen for treatment of advanced breast cancer. The randomized clinical trial is required to elucidate the efficacy of 5-fluorouracil (5-FU) or its analogues and the significance of methods for their administration in management of patients with advanced breast cancer.