Hepatic conversion of 1-(tetrahydro-2-furanyl)-5-fluorouracil into 5-fluorouracil in patients with hepatocellular carcinoma

The pharmacokinetics of 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) and its conversion into 5-fluorouracil (FUra) in liver tissue were studied in ten patients with hepatocellular carcinoma (HCC). The plasma concentration of FT after its intravenous injection (dosage: 800 mg) was computerfitted to a bi-exponential function (C = Ae-alpha t + Be-beta t), indicating a two-compartment disposition. The pharmacokinetic parameters did not significantly differ between the five patients with, and the five without cirrhosis of the liver. The plasma concentrations of FUra likewise showed no significant difference between the two groups. The rates of FT degradation in the liver tissue homogenate were similar for four of the patients with cirrhosis (0.10 +/- 0.05 mumol/g liver protein/30 min) and four of those without it (0.13 +/- 0.05). The rates of cytochrome P-450-dependent FUra formation in the microsomal fraction of liver tissue from two patients (1.1 and 1.3 nmol/mg microsomal protein/30 min) were dramatically reduced to less than half of those of two control subjects (2.4 and 2.7). The estimated rates of FUra formation in the soluble fraction (105,000 X g supernatant fraction) from the two patients (0.1 and 0.13 nmol/mg protein/30 min) were almost identical to those from the controls (0.12 and 0.14), suggesting that the rate in the soluble fraction from HCC patients may not be as strongly affected as the rate in the microsomal fraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Abnormal fluorine-18-fluorodeoxyglucose uptake in benign esophageal leiomyoma

A benign esophageal leiomyoma with abnormally increased fluorine-18-fluorodeoxyglucose uptake on positron emission tomography (PET) was resected thoracoscopically. The tumor, of which the maximum standardized uptake value of the lesion was 4.7, was well defined and 38 mm in diameter. Neither mitotic activity nor degeneration was found histologically; and immunoreactivity for CD34, CD117, MIB-1, and glucose transporter-1 was negative immunohistochemically. A diagnosis of gastrointestinal stromal tumor was ruled out by an oncogenic kinase gene mutation study. This case cautions against PET-dependent evaluation for malignant potential of esophageal submucosal tumors.     

Geographic Benefit from Decentralized Medical Education: Student and Preceptor Practice Patterns

The performance of area health education center (AHEC)-stimulated programs and decentralized education for medicine is not well understood. The Statewide Education Activities for Rural Colorado's Health (SEARCH)/AHEC project at the University of Colorado School of Medicine was examined to determine if the program had an effect on the practice location of its graduates. Practice location and specialty of graduates of the University of Colorado School of Medicine (UCSOM) classes 1980-1985 were compared for students who had participated in decentralized SEARCH/AHEC experiences versus students who had not. The majority of the graduates were practicing out of state in 1990. Non-Colorado doctors were more often practicing in rural (non-metropolitan statistical area [MSA]) counties and in towns of fewer than 2,500, 5,000 and 10,000 residents, respectively. In addition, of the 251 active patient care physicians practicing in Colorado communities of fewer than 10,000 in non-MSA counties in 1986, those who precepted UCSOM students on SEARCH rotations were more likely to have remained in their same practice location in 1992 (77.8% versus 62.1% for those who had not precepted students). This analysis of both student and preceptor practice patterns documents the value of decentralized medical education in addressing the geographic and specialty maldistribution of physicians. These results have important policy implications for funding medical education programs.     

Jejunal carcinoma with adenoma —Report of a case and review of the Japanese literature—

A rare case of jejunal carcinoma coexisting with adenoma, situated 120 cm distal to the ligament of Treitz in a 53 year old male, is reported herein. We also review cases of adenoma and carcinoma in the jejunum and ileum from the Japanese literature, and discuss the histogenesis of carcinoma of the jejunum and ileum.     

Effects of AETT-Induced Neuronal Ceroid Lipofuscinosis on Learning Ability in Rats

Abstract: The behavioral effects of ceroid-lipofuscin accumulation, induced by intraperitoneal administration of acetyl-ethyl-tetramethyl-tetralin (AETT) in Wistar rats for 3 months, were examined in the present studies. A significant increase in neuronal ceroid-lipofuscin was demonstrated neuropathologically as well as morphometrically. Although the AETT-intoxicated rats showed neither alteration of locomotor activity nor shock sensitivity, a significant impairment of learning ability, especially an acquisition trial in passive avoidance tests, was observed. Results of the present studies indicate the possibility that a diffuse lipofuscin accumulation causes a learning impairment in rats. The results also imply the possibility of a significant role of age-related lipofuscin accumulation in the dementing processes of human especially in the elderly.     

Isotopic evaluation of the metabolism of pyruvate and related substrates in normal adult volunteers and severely burned children: effect of dichloroacetate and glucose infusion

In this study we have assessed the hypothesis that there is a postreceptor defect in glucose metabolism that makes the severely burned patient unable to oxidize glucose efficiently as an energy source. The intracellular pyruvate pool was labeled by the infusion of 3-13C-lactate, and expired CO2 production and isotopic enrichment of both pyruvate and CO2 were determined to calculate the rate of pyruvate production and oxidation. 6,6-d2-Glucose and 15N-alanine were infused simultaneously to relate pyruvate kinetics and oxidation to glucose and alanine kinetics. Five normal volunteers and 10 severely burned patients (mean of 80% +/- 5% body surface burned) were studied in the basal state and during continuous (unlabeled) glucose infusion. Also, the effect of dichloroacetate, which normally stimulates pyruvate dehydrogenase activity, was assessed in both volunteers and patients. The burned patients had many of the classic metabolic responses to severe injury, including significant increases in resting energy expenditure, glucose production, and alanine release from protein breakdown. However, rather than being inhibited, the rate of pyruvate oxidation was increased approximately 300% in burned patients. Although the patients had an elevated mean concentration of lactate, stemming from increased lactate production, no deficit in pyruvate dehydrogenase activity was evident. Rather, the high rate of lactate production was apparently a consequence of the high rate of glycolysis. On the other hand, the direct pathway for synthesis of glycogen from infused glucose appeared to be impaired in burned patients. In both volunteers and patients, dichloroacetate stimulated the percent of pyruvate directed to oxidation, thereby reducing the conversion of pyruvate to other fates, including lactate. However, because there was no deficit in pyruvate dehydrogenase activity in the patients compared with normal volunteers before dichloroacetate treatment, no unique effect of dichloroacetate on glucose or protein kinetics was observed in burned patients. From these results we conclude that if there is a postreceptor defect in glucose metabolism in burned patients, it involves the pathway of direct glycogen synthesis and not the pathway of oxidation.     

Expression of the cell surface antigen detected by the monoclonal antibody A7 in pancreatic carcinoma cell lines

In a previous study, we used a murine monoclonal antibody, A7, against human colon carcinoma as a drug-carrier to treat colorectal cancer.¹ In the present study, we found that MAb A7 also reacted immunohistochemically with 73% of human pancreatic carcinoma cell lines, with the A7 antigen mainly being detected on the cell surface. However, the A7 antigen was found in only 9% of the spent media of these human pancreatic carcinoma cell lines by ELISA. On the other hand, the positive incidence of CA19-9, POA, ferritin, CEA, DU-PAN-2 and SLX in those spent media was 100%, 64%, 64%, 55%, 55% and 36%, respectively. These results suggest that the A7 antigen may only rarely be shed into the sera of pancreatic cancer patients, in which case MAb A7 could be a suitable drug-carrier in targeting chemotherapy for pancreatic cancer patients.     

Climbing exercise increases bone mass and trabecular bone turnover through transient regulation of marrow osteogenic and osteoclastogenic potentials in mice.

To investigate the relationship between the effects of bone turnover and bone marrow cell development in bone cells, we developed a mouse voluntary climbing exercise model. Climbing exercise increased bone volume and transient osteogenic potential of bone marrow. This model would be suitable for investigating the mechanistic roles of mechanical loading. INTRODUCTION: The relationship between bone mass gain and local bone formation and resorption in mechanically loaded bone is not well understood. MATERIALS AND METHODS: Sixty-five C57BL/6J mice, 8 weeks of age, were assigned to five groups: a baseline control and two groups each of ground control and climbing exercise mice for 2 and 4 weeks. Mice were housed in a 100-cm tower and had to climb toward a bottle placed at the top to drink water. RESULTS: Compared with the ground control, bone mineral density of the left femur increased in the climbing mice at 4 weeks. At 2 and 4 weeks, bone formation rate (BFR/BS) of periosteal surface, the cross-sectional area, and moment of inertia were increased in the climbing mice, whereas BFR/BS and eroded surface (ES/BS) of endosteal surface did not differ. The trabecular bone volume (BV/TV) of the proximal tibia increased in climbing mice, and osteoclast surface (Oc.S/BS) and osteoclast number decreased at 2 weeks. At 4 weeks, there were increases in BV/TV and parameters of bone formation, including mineralized surface, mineral apposition rate, and bone formation rate. In marrow cell cultures from the tibia, the number of alkaline phosphatase+ colony forming units-fibroblastic and the area of mineralized nodule formation in climbing mice were increased, and the number of osteoclast-like TRACP+ multinucleated cells was lower at 2 weeks. At 4 weeks, these parameters recovered to the levels of the ground controls. CONCLUSION: Our results indicate that climbing increased trabecular bone volume and reduced bone resorption, with a subsequent increase in bone formation. Intermittent climbing downregulates marrow osteoclastogenic cells and upregulates osteogenic cells initially, but further exercise seemed to desensitize them. Cortical envelopes were enlarged earlier, but the response seems to differ from trabecular bone.     

Enhancement of hepatitis-B surface-antigen expression by 5-azacytidine in a hepatitis-B-virus-transfected cell line.

The human hepatoblastoma-derived cell line HB611 secretes hepatitis-B surface antigen (HBsAg) and hepatitis-B e antigen (HBeAg) into the medium. Hepatitis-B-virus (HBV) DNA integrated into the cellular genome was found to be hypermethylated. When the cells were treated with 5-azacytidine for 3 days, the level of HBsAg in the medium increased, while the level of HBeAg remained constant. The level of alpha-fetoprotein (AFP) decreased with the 5-azacytidine treatment. Southern blot analysis of DNA digested with HpaII or MspI showed that 5-azacytidine treatment resulted in hypomethylation of the integrated HBV DNA, suggesting that 5-azacytidine increased HBsAg production in the cells through hypomethylation of the HBV genomic DNA.