Inhibition of liver metastases and tumor cell invasion in spontaneous liver metastasis model (LMFS) by sodium D-glucaro-delta-lactam (ND2001).

We examined the inhibitory effect of sodium D-glucaro-delta-lactam (sodium 5-amino-5-deoxy-D-glucosaccharic acid-delta-lactam: ND2001) upon liver metastases of the LMFS tumor. A permanent cell line, LMFS, was established from a spontaneously occurring murine retroperitoneal tumor of BALB/c mouse origin, and after a subcutaneous injection, the LMFS cells proliferated at the inoculation site (100% take) with liver metastases. ND2001 had little effect on the cell growth, cell cycle and phagokinesis of the LMFS cells in vitro. However, when the invasive activity was measured by the Boydem chamber method, the number of LMFS cells was reduced, with inhibition rates of 98.0%. After the LMFS cells treated with ND2001 in vitro, the numbers of hepatic metastases of subcutaneous inoculation of treated cells were reduced dose-dependently, and those of intravenous inoculation were not found by microscopical study. When the LMFS tumor-bearing mice were treated with ND2001 (0, 30, 100 mg/kg/d) from day 1, ND2001 (30 mg/kg) inhibited the liver metastases with a rate of 56.4%, and when given from day 15, ND2001 (100 mg/kg) inhibited with a rate of 47.5%. But ND2001 showed neither cytocidal nor anti-tumor activity. Combination therapy of primary tumor resection and ND2001 administration revealed that preoperative use of ND2001 was more effective in preventing liver metastases. These results suggested that ND2001 might have a potential use as an anti-metastatic agent for operative patients without metastasis.

[Effects of HCFU and TNP 470 on liver metastasis of BALB/c retroperitoneal sarcoma (LMFS)].

Combination therapy using HCFU and TNP 470, which inhibits angiogenesis, was examined for effectiveness against the footpad injection model of LMFS tumor. This LMFS, a retroperitoneal sarcoma of BALB/c mice, proliferated at the inoculation site (100% take) and all mice operated on after day 15 had spontaneous metastatic nodules in the liver. Mice with the LMFS tumor were given HCFU and 5-FU (5 days/week), and/or TNP 470 (3 days/week) from day 3 for 3 weeks and sacrified at day 28 under anesthesia. Seven of 10 mice receiving 5-FU and TNP 470 died from the side effects of the drugs. Mean tumor weight and liver metastatic nodules were determined and compared with a control group. The results were as follows: HCFU group: 94.6%, 11.8%, 5 FU group: 73.9%, 28.8%, TNP 470 group: 67.6%, 44%, HCFU and TNP 470 group: 33.3%, 6.4%. Mice with LMFS were given HCFU and/or TNP 470 from day 3 for 4 weeks. The foot on the injected side was amputated on day 15, and the animals were sacrified on day 35. Liver metastatic nodules compared with those of the operation (OP) group as follows: OP + HCFU group: 14.4%, OP + TNP group: 39.1%, and OP + HCFU + TNP 470 group: 5.4%. Histologically, 5 of 5 mice of the OP group, 3 of 5 of the OP + HCFU group, 4 of 5 of the OP + TNP 470 group and 1 of 5 of the OP + HCFU + TNP 470 group had liver metastases. These results show that while either HCFU or TNP 470 is effective by itself, a combination of these drugs is more effective against liver metastasis.

Quantitative rest technetium-99m tetrofosmin imaging in predicting functional recovery after revascularization: comparison with rest-redistribution thallium-201.

OBJECTIVES: This study was undertaken to 1) compare the regional myocardial tracer distributions between rest technetium (Tc)-99m tetrofosmin and rest-redistribution thallium (Tl)-201 images in patients with coronary artery disease and left ventricular dysfunction; and 2) assess the comparative values of these agents for predicting functional recovery after revascularization. BACKGROUND: Tc-99m tetrofosmin is a new myocardial perfusion imaging agent, but its role for detecting viable myocardium is still unclear. METHODS: Thirty-six patients with coronary artery disease and left ventricular dysfunction underwent rest Tc-99m tetrofosmin, rest-redistribution Tl-201 and gated blood pool scintigraphy. In 21 patients with successful revascularization confirmed by follow-up angiography, gated blood pool scintigraphy was repeated after revascularization. Optimal threshold cutoffs to separate reversible from irreversible dysfunction were determined by receive operating characteristic analysis. RESULTS: Regional Tc-99m tetrofosimin activity highly correlated with redistribution Tl-201 activity (r = 0.93). The diagnostic performance for predicting functional recovery, as measured by the area under the receiver operating characteristic curves, measured 0.66 +/- 0.07 (mean +/- SD) for Tc-99m tetrofosmin and 0.67 +/- 0.07 for Tl-201 (p = 0.60, 96.7% power to detect difference in area of 0.10). The optimal threshold cutoffs for viability were considered to be 50% of peak activity for Tc-99m tetrofosmin and 55% of peak activity for Tl-201. The positive and negative predictive values for reversible dysfunction were, respectively, 69% and 82% for Tc-99m tetrofosmin and 69% (p = 0.99 vs. Tc-99m tetrofosmin) and 71% (p = 0.66 vs. Tc-99m tetrofosmin) by Tl-201. CONCLUSIONS: The diagnostic performance of quantitative rest Tc-99m tetrofosmin imaging in predicting functional recovery after revascularization is comparable to that of rest-redistribution Tl-201.

[Surgical treatment for ascending aortic aneurysm using a transthoracic left ventricular venting].

Three patients with ascending aortic aneurysms underwent graft replacement using deep hypothermic circulatory arrest with continuous retrograde cerebral perfusion. In all three cases, preoperative radiographic examination revealed that the aneurysm was large, thin, and adherent to the back of the sternum. For this reason, left ventricular venting was performed through a left thoracotomy before median sternotomy, to decrease both the risk of rupture of the aneurysm and the difficulty of cannulation. This new method, called transthoracic left ventricular venting, was very useful for performing a median sternotomy under hypotensive and hypothermic conditions adequate to reduce the risk of rupture and to manage any rupture immediately through deep hypothermic circulatory arrest.

Venous reconstruction using hybrid vascular tissue composed of vascular cells and collagen: tissue regeneration process.

In this study, a tubular hybrid vascular tissue composed of vascular cells and collagen was implanted as a venous substitute, and its remodeling process was histologically investigated. First, a hybrid medial tissue was prepared by pouring a cold mixed solution of canine jugular smooth muscle cells (SMCs) and Type I collagen into a tubular glass mold and subsequent incubation at 37 degrees C. Culture in medium for 10 days produced a dense tubular tissue. Seeding of jugular endothelial cells (ECs) onto the luminal surface of the tissue produced a hybrid vascular tissue with a hierarchical structure. These vascular tissues (inner diameter, 7 mm; length, 3 cm; wall thickness, 1 mm; n = 14) were implanted autologously in the canine posterior vena cava wrapped in Dacron mesh for up to 24 wk. Nine of 14 grafts were patent throughout implantation. In patent grafts, monolayered ECs were oriented in the direction of blood flow at 1 wk. Circumferentially oriented SMCs accumulated at the subendothelial layer and ingrown fibroblasts were sparsely distributed throughout the wall at 12 wk. Contractile phenotype of SMCs was evident at 24 wk. Collagen fibrils, which were sparsely distributed at an early period of implantation, gradually assembled to form fibrous meshes at 24 wk. Sheet-like elastic lamellae were also observed at this time. Marked wall thinning was observed at 12 and 24 wk. The resultant tissues became highly dense. The specific gravity of tissues increased with time, and reached those of natural vessels at 24 wk. Tissue remodeling progressed in a time-dependent manner and appeared to be almost complete within 6 mo of implantation.

Identification of two novel Dictyostelium discoideum cysteine proteinases that carry N-acetylglucosamine-1-P-modification.

Dictyostelium discoideum makes multiple developmentally regulated lysosomal cysteine proteinases. One of these, a lysosomal enzyme called proteinase I, contains a cluster of GlcNAc-alpha-1-P-Ser residues. We call this phosphoglycosylation. To study its function, a cDNA library from vegetative cells was screened, and two novel cysteine proteinase clones were characterized (cprD and cprE). Each of them has highly conserved regions expected for cysteine proteinases, but unlike any other, each has a serine-rich domain containing three distinct motifs, poly-S, SGSQ, and SGSG. cprD and cprE cDNAs were overexpressed in Dictyostelium and the active enzymes identified. cprD codes for a protein of approximately 36 kDa (CP4), which is recognized by monoclonal antibodies against GlcNAc-1-P and fucose. cprE corresponds to a 29-kDa protein, which is recognized by antibodies against GlcNAc-1-P. mRNA for both enzymes is present in the vegetative phase and increases during growth on bacteria but decreases throughout development. When the formation of the fruiting body is complete the mRNA for both messages is detected again but in very low levels. Having cloned cDNAs for proteins that carry GlcNAc-1-P should allow us to probe the function of the carbohydrate in these putative lysosomal enzymes.

Clinical use of low porosity woven ultrafine polyester fiber grafts.

A woven fabric graft made of ultrafine polyester fibers (UFPF) (Toray Graft, water porosity: 100 ml/min/cm2:120 mm Hg H2O) was clinically applied in 81 cases (28 thoracic aortic aneurysms, 6 thoracoabdominal aortic aneurysms, 42 abdominal aortic aneurysms, and 5 atherosclerotic obstructions of the peripheral arteries). Eight patients died after surgery due to causes unrelated to the graft. The other 73 patients were in good condition after surgery. For operations requiring extracorporeal circulation, the graft was presealed with human albumin. For the abdominal aortic aneurysms, the graft was preclotted in situ with nonheparinized autoblood after the completion of the proximal anastomosis. It took about 2 min to complete the preclotting. A nonsealed graft was used for the reconstruction of peripheral arteries for the intraaortic balloon pumping procedure. The graft was easy to handle. There was no cut edge fraying problem with the graft in any direction of cutting. Even after presealing, the graft was soft and pliable enough to enable easy adaptation and anastomosis. Just after implantation, bleeding was minimal from the graft wall, anastomotic sites, and suture pores, and it stopped spontaneously. These clinical data showed that the woven UFPF graft exhibited both easy handling despite in spite of low porosity and safe application in the reconstruction of arterial systems even under totally heparinized conditions during extracorporeal circulation.

An asymptomatic, normotensive sipple syndrome patient with glucose intolerance and hypercholesterolemia, and her kindred.

The proband, a 42-year-old woman without any symptoms or hypertension, was admitted for examination of accidentally discovered bilateral adrenal masses. Physical examination disclosed bilateral nodular goiter and mild sinus tachycardia. Pheochromocytomas and medullary thyroid carcinomas were revealed by biochemical and histopathological examinations. Hypercholesterolemia and abnormal glucose metabolism returned to normal after bilateral total adrenalectomy and thyroidectomy. Screening examination showed four affected family members. Three of them were also asymptomatic and normotensive. In pheochromocytoma patients, normotension, hypercholesterolemia, and impaired glucose metabolism might be signs of excess secretion of epinephrine rather than norepinephrine.

Different rates of acceptance of health examination among the people under 2 separate health insurance programs in Japan.

The entire population in Japan is covered by either workplace-based health insurance program or region-based health insurance program. While both programs were originally for curative medical care, only the former program has recently extended its financial support to preventive health examination. The attitude of the people toward health examination was studied in Miyagi prefecture in north-east Japan by questionnaires with more than 32,000 respondents to examine whether the difference in health insurance reflect on the rates of acceptance of 4 health examination items (i.e., blood pressure measurement, chest x-ray taking, and 2 screening tests for stomach and cervical cancer). Throughout the 4 items, the rate of acceptance was higher among those who were covered by workplace-based health insurance than among those covered by regional health insurance. The difference is large for the insured and less so for the family dependents of the insured. Further analysis for the preferred opportunities for health examination such as personal examination at clinics in contrast to region-based mass examination showed that the weight of clinics was quite large for the insured of national health insurance and their family dependents (i.e., 50% or even larger) but it was less so for the people covered by workplace-based insurance.

Urban-rural difference in the acceptance of mass health examination in north-eastern Japan.

Over 40,000 residents (less than or equal to 40 years of age) in a city (Sendai; the city group), a town (Shiroishi; the town group) and two villages (Wakuya and Tajiri; the village group) in Miyagi prefecture in north-eastern Japan responded in a questionnaire survey on their attitude towards mass health examinations (i.e., whether they underwent in the previous year and if so where) on 4 items of blood pressure measurement, chest x-ray examination and screening tests for stomach and cervical cancer. The coverage rates were about 70% on an average both for blood pressure measurement and for chest x-ray examination, whereas the rates for cancer screening were between 30-40%. As for the opportunity of the former two examinations, the workplace mass examination played a large role in the case of the city and town groups (especially among men but not women) in addition to visit to clinics, in contrast to the case of the village group in which people depended much on regional mass examination service. The trend was essentially reproducible in stomach cancer screening although the over-all coverage rate was low, whereas women in the three groups almost exclusively utilized clinics for cervical cancer screening with one exception that the mobile unit service appeared to be equally accepted in the village group.

[Relation between plasma Ara-C and intracellular Ara-CTP levels by intermediate dose and high dose Ara-C administration in the treatment of AML].

Plasma level of cytosine arabinoside (Ara-C) and intracellular cytosine arabinoside triphosphate (Ara-CTP) in peripheral blood and bone marrow were measured in 8 patients with non treated acute myelogenous leukemia. Ara-C was administered by 1 hr infusion (3 g/m2 and 500 mg/m2) and was followed for 12 hrs. The AUC of Ara-C in plasma following 3 g/m2 infusion were greater than the 500 mg/m2 (p less than 0.05). Intracellular Ara-CTP in peripheral blood following 3 g/m2 and 500 mg/m2 infusions were on the same level, after 1 hr. But AUC of intracellular Ara-CTP following 3 g/m2 infusion was greater than 500 mg/m2. There was a correlation between AUC of Ara-C in the peripheral blood (p less than 0.01). Intracellular Ara-CTP in the bone marrow and peripheral blood showed a similar level. Intracellular Ara-CTP in bone marrow was lower than in peripheral blood, however, there was no correlation between intracellular Ara-CTP in bone marrow and in peripheral blood.

[Clinical and pharmacokinetic studies of high dose N4-behenoyl-1-beta-D-arabinofuranosylcytosine].

Effect of high dose of N4-behenoyl-1-beta-D-arabinofuranosylcytosine (BH-AC) was studied clinically and pharmacologically in non-Hodgkin's lymphoma and acute leukemia. The schedule of drug administration consisted of daily i.v. infusion for 5 consecutive days. The daily close was initiated with 500 mg/m2 which was escalated up to 1300 mg/m2. Eruption was found to be dose-limiting toxicity and there was no myelosuppression. The plasma concentration curve of BH-AC showed a biphasic curve. The half-lives of the initial phase (t1/2 alpha) and the second phase (t1/2 beta) by the administration (1 hr iv infusion) of 700 mg/m2 were 1.08 and 3.65 h respectively. The plasma 1-beta-D-arabinofuranosylcytosine was detected for 12-24 hr after infusion (Cmax: 0.26 microgram/ml).

[Clinical study of non-Hodgkin's lymphoma--results of the Kanazawa University-Kurume University Cooperative Study on Malignant Lymphomas].

Ninety-two patients with previously untreated non-Hodgkin's lymphoma (NHL) were studied multidisciplinarily. The high incidence of NHL in elderly men (older than 60 years) was confirmed. With regard to the initial site, 51 patients (55.5%) were affected in the nodal region while other patients were affected in the extranodal or Waldeyer's ring region. Eighty-two patients (89.1%) were diagnosed as having diffuse lymphoma, and 47 of these patients were further classified into large cell type (LSG classification). Surface marker analysis revealed that the incidence of B cell-type NHL was twice as high as that of T cell-type NHL. All patients were entered into a randomized trial of radiotherapy and/or combination chemotherapies (ACOP, ACOP-E and AclBEP regimens) according to clinical stage. More than 90% of the patients with early-stage NHL achieved complete remission (CR), and the CR rate for patients with advanced-stage disease was about 50%. All patients with CS I NHL are still alive at 27 months after diagnosis, and the survival rate of patients with CS II NHL at 35 months after diagnosis is 80%. However, the median survival time of patients with advanced-stage disease was estimated to be 16 months.

The constant plasma 18-hydroxycorticosterone to aldosterone ratio: an expression of the efficacy of corticosterone methyloxidase type II activity in disorders with variable aldosterone production.

Aldosterone and 18-hydroxycorticosterone (18-OHB) are produced by the adrenocortical zona glomerulosa. Under normal conditions, plasma 18-OHB levels parallel and are influenced by the same trophic factors that regulate aldosterone production. To evaluate corticosterone-methyl-oxidase II activity, the final step of aldosterone biosynthesis, in conditions associated with chronic derangements of the pituitary-adrenal and/or renal-adrenal axis, we measured the plasma 18-OHB to aldosterone ratio, cortisol, PRA or plasma renin concentration, and potassium (K) in 104 such patients and 15 normal subjects. The 18-OHB to aldosterone ratios in the pituitary-adrenal group were not significantly different from normal regardless of elevated or reduced ACTH and/or cortisol levels [patients with Cushing's syndrome, 3.55 +/- 0.68 (+/-SE); ACTH deficiency, 2.03 +/- 0.34; 21-hydroxylase deficiency, 3.09 +/- 0.23; normal subjects, 2.50 +/- 0.15]. The renal-adrenal group also had normal ratios regardless of plasma renin concentration and K levels [patients with aldosterone-producing adenomas, 2.85 +/- 0.15; idiopathic hyperaldosteronism, 2.14 +/- 0.19; salt-losing nephropathy, 3.06 +/- 0.54; Bartter's syndrome, 2.89 +/- 0.20; isolated (hyporeninemic) hypoaldosteronism, 3.20 +/- 0.39]. Only in patients with 17 alpha-hydroxylase deficiency (230.1 +/- 118.6) was the ratio abnormally high. Chronic perturbations of aldosterone production by ACTH, the renin-angiotensin system, and/or K did not alter this last step of aldosterone biosynthesis (corticosterone-methyloxidase II), as defined by their plasma concentrations. Any influence of these trophic factors must be proximal to the site of 18-OHB production.

Regulation of the mineralocorticoid hormones in adrenocortical disorders with adrenocorticotropin excess.

Chronic stimulation by adrenocorticotropin (ACTH) of the adrenal cortex produces different plasma mineralocorticoid hormone (MCH) patterns, depending on the amount of glucocorticoid hormones (cortisol) concurrently generated and the degree of activation of the renin angiotensin system (RAS). Patients with Cushing's disease or the ectopic ACTH-excess syndrome have normal or low production of the MCHs, aldosterone and 18-hydroxycorticosterone (18-OHB), by the zona glomerulosa (ZG), elevated cortisol and deoxycorticosterone (DOC) levels, and high-normal to elevated production of the MCHs corticosterone (B) and 18-hydroxydeoxycorticosterone (18-OHDOC) by the zona fasciculata (ZF). Prolonged administration of superphysiologic doses of ACTH to normal subjects yields similar patterns. Patients with simple virilizing 21-hydroxylase deficiency (21-OHD) have impaired ZF production of B and 18-OHDOC and elevated DOC, 18-OHB, and aldosterone secretion secondary to the superimposed RAS stimulation of the ZG. Patients with 17 alpha-hydroxylase deficiency (17 alpha-OHD) have elevated levels of the ZF MCHs DOC, B, 18-OHDOC, and 18-OHB and a functionally suppressed ZG. Patients with 11 beta-hydroxylase deficiency (11 beta-OHD) have only elevated production of DOC by the ZF and suppressed RAS and aldosterone. A significant negative correlation between cortisol and aldosterone concentrations suggests that cortisol is involved in the ACTH-mediated inhibition of aldosterone formation.

The mineralocorticoid hormone pathways in hypertension with hyperaldosteronism.

Simultaneous measurement of the 0800-hr plasma concentrations of deoxycorticosterone (DOC), corticosterone (B), 18-hydroxycorticosterone (18-OHB), aldosterone, 18-hydroxydeoxycorticosterone (18-OHDOC) and cortisol (F) in four types of primary aldosteronism provides evidence for primary adrenal disease. Elevated DOC with normal F concentrations in the presence of elevated 18-OHB and aldosterone, and suppressed renin concentration suggests a primary adrenal abnormality of the zona glomerulosa (ZG). Steroid production by the zona fasciculata (ZF), F, 18-OHDOC, and most often B, is normal. These patterns exist only for primary adrenal hyperplasia, aldosterone-producing adenoma (APA), and aldosterone-producing adrenocortical carcinoma (AP-Ca). Elevated DOC levels are rarely found in patients with idiopathic hyperaldosteronism (IHA or adrenal hyperplasia) and suggest that IHA is not a primary adrenal disorder and should be excluded from the syndrome of primary aldosteronism as they have been heretofore.