Anticancer activity and toxicity of S-1, an oral combination of tegafur and two biochemical modulators, compared with continuous i.v. infusion of 5-fluorouracil

S-1 is an oral combined form of 1 M tegafur [a prodrug of 5-fluorouracil (5-FU)], 0.4 M 5-chloro-2,4-dihydroxypyridine (a reversible inhibitor of dihydropyrimidine dehydrogenase) and 1 M potassium oxonate (an inhibitor of orotate phosphoribosyltransferase). S-1 has been shown to exert a potent antitumor effect with low gastrointestinal toxicity in experimental tumor models. We have therefore compared the antitumor effect of oral S-1 with that of continuous infusion of 5-FU in rats bearing transplants of human and murine tumors. Almost complete inhibition of the tumor growth was obtained on 7 day schedules in Yoshida sarcoma-bearing rats by consecutive administration of 30 mg/kg/day of oral S-1 and 40 mg/kg/day infusion of 5-FU. However, a significant difference between the incidence of toxicities of S-1 and 5-FU, including body weight loss and diarrhea, was noted. The rats given the 5-FU infusion had marked weight loss and severe diarrhea, while those given oral S-1 had neither. Although about 50% inhibition of the tumor growth was attained with 15 mg/kg/day of oral S-1 and 30 mg/kg/day infusion of 5-FU in nude rats with xenografted human colon cancer (KM12C), the rate of body weight loss in the 5-FU-treated group was distinctly higher than in the S-1-treated group. The ratio of the 5-fluoronucleotide concentrations in gastrointestinal tissue to that in the tumor was lower in the S-1-treated rats than in the 5-FU-treated rats. In conclusion, the results suggest that oral S-1 might be more effective in the treatment of cancer patients than continuous infusion of 5-FU, from the standpoint of antitumor potency and toxicity.     

Hormonal and metabolic effects of somatostatin in diabetic patients submitted to an i.v. arginine infusion

In French-speaking Quebec, implantation of behaviour therapy in psychiatric hospitals has been difficult because psychiatrists' training was and still is almost exclusively based on psychoanalytic therory. For this reason, many psychotherapists do not use the knowledge derived from laboratory experiments and only rely on their clinical judgement. Prejudiced by their professional identity, many psychiatrists believe that behaviorists manipulate and control patients, mechanize therapy, deny the importance of interpersonal relationships and only use punitive techniques. After refuting these arguments, the author describes the practical difficulties encountered when implanting behaviour therapy in a psychoanalytic milieu, as well as the advantages of a better understanding between these two schools, which might lead to psychiatry becoming more scientific, more human and closer to daily reality.     

Augmentation of the neuromuscular blocking effects of cisatracurium during desflurane, sevoflurane, isoflurane or total i.v. anaesthesia

We recently performed a laparoscopic cholecystectomy on three patients receiving preoperative oral anticoagulant therapy. The patients requiring anticoagulants for pre-existing cardiac conditions have the following risks at surgery: thromboembolism, hemorrhage, endocarditis, and cardiopulmonary dysfunction. In patients receiving anticoagulant therapy, one must thus maintain a balanced international normalized ratio of the prothrombin time to prevent thromboembolism or hemorrhage. Warfarin sodium was discontinued preoperatively in all patients. Heparin sodium was individualized according to each patient's risk of thromboembolism. As a result, these patients all underwent a laparoscopic cholecystectomy without complications. Attention was paid to achieve hemostasis in the operative field and the trocar inserted sites during the procedure. The administration of warfarin sodium was resumed on the first postoperative day in all patients. Restarting warfarin sodium early also helps to simplify postoperative management. A broad spectrum of antibiotic therapy was also used to reduce the risk of endocarditis. Each patient's cardiopulmonary function was carefully monitored. The minimal invasion experienced during a laparoscopic cholecystectomy may thus facilitate the management of gallstones in patients receiving systemic anticoagulation treatment based on the findings of this limited series.     

0.45% saline and 5% dextrose in water, but not 0.9% saline or 5% dextrose in 0.9% saline, worsen brain edema two hours after closed head trauma in rats

In this study, we examined the effect of four i.v. fluids (250 mL/kg) on blood glucose and osmolality and brain tissue specific gravity after closed head trauma (CHT) in rats. CHT was delivered at Time 0; blood was sampled at 60 min; fluid infusion began at 75 min and ended at 105 min. Blood was again sampled at 105 and 120 min, and brain tissue specific gravity was determined at 120 min. Five groups (one control and four fluid-treated groups) received CHT, and five other groups (one control and four fluid-treated) did not (n = 9 in each group). 0.45% saline (1/2 NS) and 5% dextrose in water (D5W) accentuated the decrease of brain tissue specific gravity (1.0366 +/- 0.0025 and 1.0368 +/- 0.0028, respectively; mean +/- SD) caused by CHT (1.0395 +/- 0.0036), but 5% dextrose in 0.9% saline (D5NS) and 0.9% saline (NS) did not (1.0431 +/- 0.0042 and 1.0389 +/- 0.0049, respectively). In addition, 1/2 NS decreased blood osmolality (248 +/- 6 mOsm/L), D5W increased blood glucose (1095 +/- 173 mg/dL), D5NS increased blood osmolality (350 +/- 5 mOsm/L) and glucose (1695 +/- 76 mg/dL), and NS caused no significant change. We conclude that administering hypoosmolar i.v. fluids after CHT causes a significant worsening of cerebral edema 2 h after CHT. Implications: We previously reported worse neurological outcome and/or mortality after closed head trauma in rats when 5% dextrose in water or 0.45% saline was given i.v. compared with 0.9% saline or 5% dextrose in 0.9% saline. The present results and our previous findings indicate that worsening of outcome after closed head trauma in rats may be caused more by edema formation than by hyperglycemia.     

Autoradiographic and scintillationspectrographic studies of 14C-zolimidine in rats after i.v. and oral application (author's transl)

The relative distribution of radioactivity after i.v. (5 mg/kg) and oral (25 mg/kg) application of 14C-Zolimidine [2-(p-methyl-sulfonylphenyl)-imidazo-(1,2-a)-pyridine-2-14C] was examined in male rats by whole-body autoradiography and scintillation fluid spectrometry. 14C-Activity was remarkably concentrated in the stomach of i.v. treated animals, probably as a result of secretion from the pyloric and/or fundic part of the mucous membrane. 14C-Zolimidine also accumulated in the aortic vascular walls, the adrenal gland, and in the excretory organs, liver, kidney, and intestine, after both routes of drug administration. Much less radioactivity could be measured in brain and spinal cord. The estimation of nearly 80% gastrointestinal absorption of 14C-zolimidine and the suggestion of one or more metabolites were in accordance with previously reported results. The elimination of radioactivity from brain occurred more rapidly than from other organs. No striking results were found in the reproductive organs of the rats.     

Variations of glucose, fructose, sorbite and electrolyte concentration following intravenous or intraperitoneal administration of sorbite-electrolyte solution to cattle and sheep

Different quantities of sorbite-electrolyte solution were intravenously administered to eight heads of cattle and four heads of sheep (application values being 50 g sorbite, 0.3049 g MgCl2-6H2O, 0.3728 g KCl, 0.5477 g CaCl2-6H2O, 5.265 g NaCl, 6.804 g sodium acetate-3H2O with 1,000 ml distilled water). Different rises of sorbite, fructose, and glucose were recorded from the blood plasma. Certain manifestations of incompatibility and intolerance phenomena were observed, among them increase of cardiorespiratory activity and muscular tremor. Those findings were obtained primarily from animals which exhibited also strong rise in glucose concentration. One of the sheep died. Larger quantities of solution (2,000 ml or 4,000 ml) were intraperitoneally applied to ten heads of cattle and tolerated by them with no reaction. Sorbite in blood plasma usually reached its maximum two or three hours from application, however, without any rise of fructose or glucose. Slow drip infusion or intraperitoneal infusion are the techniques recommended for application of the above sorbite-electrolyte solution to ruminants.     

Effects of varying levels of duodenal or midjejunal glucose and 2-deoxyglucose infusion on small intestinal disappearance and net portal glucose flux in steers

Six crossbred steers (261 +/- 18 kg BW) fitted with hepatic portal, mesenteric venous and arterial catheters, and duodenal, midjejunal, and ileal cannulas were used in a replicated 3 x 3 Latin square design to determine the effect of varying levels and site of glucose plus 2-deoxyglucose (2DG) infusion on net portal-drained visceral flux. Steers were fed chopped alfalfa in six equal portions daily at 1.5% of BW. Glucose (0, 9, or 18 g/h) and 2DG (0, 1, or 2 g/h) were infused continuously through the duodenal or midjejunal cannula (two infusion sites) at total glucose plus 2DG infusion rates of 0, 10, or 20 g/h. Arterial and portal blood samples were taken simultaneously at 20-min intervals from 5 to 9 h of infusion. Portal blood flow was determined by continuous infusion of p-aminohippurate and net flux was calculated as venous-arterial concentration (PA) difference times blood flow. Arterial concentration of glucose was not affected (P > .10) by glucose plus 2DG infusion, whereas arterial concentration of 2DG was greater (P < .05) when glucose plus 2DG was infused into the duodenum and increased (linear, P < .10) as amount of glucose plus 2DG infused into both the duodenum and midjejunum increased. Net portal flux and PA difference of glucose and 2DG were greater (P < .05) when glucose plus 2DG was infused into the duodenum. Although 2DG was infused at 10% of the total glucose plus 2DG infusion, it accounted for only 1.7 and .7% of the glucose plus 2DG appearing in portal blood when glucose plus 2DG was infused at 10 and 20 g/h, respectively. We conclude that glucose is more readily absorbed across the proximal-half than the distal-half of the small intestine, and that passive diffusion is a minor route of glucose absorption.     

Struvite calculi dietetics: 2. Effect of ammonium chloride and carbonates on the acid-base and mineral balance of cats

Six healthy adult cats were fed a basal minced beef meat and rice diet with varying amounts or combinations of acidifying and alkalizing additives (ammonium chloride, calcium and sodium carbonate). The base excess in the food (mmol/kg dry matter) was calculated (data on food compounds in g/kg dry matter) as follows: base excess = 49.9*Ca + 82.3*Mg + 43.5*Na + 25.6*K - 64.6*P - 13.4*Met-16.6*Cystine -28.2*Cl. It amounted to between +305 and -1079 mmol/kg dry matter. Urine and blood pH as well as balance of minerals and water were determined in the cats. The mean urine pH ranged between 6.1 and 7.8. There was a highly significant correlation between the base excess in the food and the mean urine pH. The regression line was linear down to a base excess in the diet of about -400 to -500 mmol/kg dry matter and a pH in the urine of 6.2. The postprandial increase of urine pH was suppressed either by large amounts of ammonium chloride (> 780 mmol/kg dry matter) alone or in combination with calcium carbonate, but not in combination with sodium carbonate. The relationship between the decrease of the blood pH and the amount of ammonium chloride added to the diet was more marked than the relationship between blood pH and base excess in the food. In order to avoid health risks by long term application of acidifying diets it is recommended to formulate struvite diets with low base excess in such a way, that they contain as few alkalizing compounds as possible, which must be neutralized by acidifiers.     

Is a lag-storage curve an early sign of diabetes? Early insulin responses to i.v. glucose in normal subjects, mild maturity-onset diabetics and patients with lag-storage curves

Because it is frequent and variable by sex, age and culture, manifest aggression in dreams appears to be an important research area. A comparison was made between dreamed aggressions for Americans (Hall and Domhoff 1963) and for Zapotecs, collected and analysed by the writers. Similarities and differences revealed in the comparison, suggest the importance of cultural factors in manifest dreamed aggression, along with sex and age. Multivariate analyses of carefully collected cross-cultural data will be necessary before adequate assessments can be made of the relative importance of these variables in dreams, more clearly establishing relationships between wakeful and dreamed experiences.     

''Exponential peeling'' of ventilatory transients following inhalation of 5, 6 and 7% CO2

The 'exponential peeling' technique has been applied to minute ventilation and tidal volume transients occurring after the abrupt removal of 7, 6 and 5% CO2 in inspired air. These transients, in many cases, were found to be composed of three exponential components, each contributing to the total ventilatory response and each having individual time responses. Gelfand and Lambertsen (1973) have attributed these components to the peripheral chemoreceptors as a group and to two central chemoreceptors. Statistical analysis to determine the constancy of the contribution of the three components over the range of CO2 values studied showed that, although the values for each at the different stimulus levels were not significantly different, the great subject-to-subject variation in the data precluded a firm conclusion about the constancy of the components. Because of a number of considerations it was concluded that exponential peeling of respiratory transients following abrupt removal of CO2 inhalation is not a satisfactory way to approach the problem of the numbers, relative contributions and time responses of the various receptor groups comprising the respiratory controller.     

Low-dose oral etoposide and subcutaneous injection of low-dose cytosine arabinoside (Et-A non i.v.) with or without minimum anthracycline for refractory acute non-lymphoblastic leukemia

Low-dose oral etoposide (50 mg for 10 to 14 days) and low-dose subcutaneous injection of cytosine arabinoside (15-20 mg/12 hours for 14 to 17 days) (Et-A non i.v.) were given to refractory acute non-lymphoblastic leukemia patients. Case 1 was a 47-year-old woman who had a relapsed M0. B-DOMP therapy failed but she recovered from severe infection. She had to go home to take care of her children. Et-A non i.v. was given for 14 days and 11 mg of mitoxantrone was added on the 3rd day. She achieved a complete remission (CR). Case 2 was a 72-year-old woman classified M4. Low-dose cytosine arabinoside (Ara-C) with additional daunorubicin (DNR) therapy failed. She became weaker due to the gastrointestinal toxicity of DNR. Et-A non i.v. was tried. Oral etoposide (Et) for 10 days and Ara-C for 14 days proved effective, and she achieved CR. Case 3 was a 59-year-old man with M4 developed from myelodysplastic syndrome, complicated with infection. Ara-C low-dose therapy was begun, but it was not effective. It was switched to Et-A non i.v., 40 mg of DNR was added, with 12 mg of mitoxantrone and double administration of 3 mg of vindesine. He also achieved CR. Et-A non i.v. therapy is effective and available for induction therapy with low toxicity and convenient to daily life.     

Differential effects of sucrose, fructose, glucose, and lactose on crying in 1- to 3-day-old human infants: Qualitative and quantitative considerations.

Assessed the potency of different sugars as calming agents in human infants. Five 0.1-ml aliquots of 0.51M sucrose, fructose, glucose, or lactose were presented to 1- to 3-day-old infants who were crying spontaneously. Sucrose and fructose were equally effective calming agents, glucose slightly less so. Lactose, the milk sugar, was not at all effective and did not reduce crying any more than did water. In fact, some babies cried more when given lactose. A 2nd experiment established quantitative, dose-response functions for sucrose as a calming agent: 0.17M, 0.42M, and 0.51M sucrose reduced crying equally effectively. Moreover, crying reduction was not differentially affected by the volume of ingested sucrose, because 0.2 ml of 0.34M sucrose was as effective as 0.6 or 1.0 ml of 0.34M sucrose. Results suggest that sucrose calms in a stepwise manner with a flat suprathreshold function and that the calming basis of milk must be sought in components other than its sugar. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Detection of linguistic ambiguity by reflective, impulsive, fast/accurate, and slow/inaccurate children.

Investigated the relation of conceptual tempo to children's detection of linguistic ambiguity. After completing the Matching Familiar Figures Test, 96 4th and 7th graders were classified as reflective, impulsive, fast/accurate, and slow/accurate and were asked to paraphrase the meaning of ambiguous sentences and then to indicate their meaning through a selection of pictures. Results indicate that reflective children were more successful than impulsive and slow/inaccurate children (a) in spontaneous paraphrasing of the multiple meanings of sentences and (b) in detecting the various ambiguities on the picture measure. In contast, on the paraphrase measure, prompting by the examiner to consider alternative meanings for the sentences eliminated differences among conceptual tempo groups. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Biochemical characterization of human osteoclast integrins. Osteoclasts express alpha v beta 3, alpha 2 beta 1, and alpha v beta 1 integrins

The study of osteoclast integrins has been previously hampered by the lack of a source of large numbers of purified osteoclasts. Osteoclastoma, a human giant cell tumor of bone, supplied a rich source of osteoclasts within a tissue containing many diverse cell types. Osteoclastoma integrin immunostaining confirmed the presence of the integrin alpha v beta 3 complex and the alpha 2 and beta 1 integrin subunits on osteoclasts. However, weak integrin expression, for example with alpha v beta 5, was difficult to interpret. Purification with magnetic beads coated with vitronectin receptor monoclonal antibody (13C2) enabled osteoclast membranes to be isolated with high purity and yield (57%) from osteoclastoma tissue. Positively (osteoclast-enriched) selected membranes were biochemically assessed for integrin expression by immunoprecipitation and visualization by non-radioactive enhanced chemiluminescence. alpha 1, alpha 4, alpha 6, alpha 8, alpha M, alpha X, gpIIb, beta 4, beta 6, and beta 8 integrin chains were undetectable at a sensitivity of 1 ng. alpha 3, alpha 5, alpha L, beta 2, and alpha v beta 5 were found in the negatively selected osteoclastoma tissue but not in the positively purified osteoclast membranes. The presence of alpha v beta 1 and alpha 2 beta 1 dimers was demonstrated biochemically on the immunoisolated osteoclast membranes. Osteoclast alpha v beta 3 isolation by Arg-Gly-Asp (RGD) affinity chromatography for NH2-terminal amino acid sequencing confirmed that the osteoclast vitronectin receptor was identical to that previously characterized on other cell types. In situ hybridization using human alpha v riboprobes in osteoclasts from human and rodent bone further demonstrated the high level and specificity of expression of alpha v vitronectin receptor in osteoclasts.     

Nitrogen metabolism of broilers fed 15-N labeled wheat.5. Skin, feathers and 15-N balance

In the present study 17 four-week-old broilers received a ration supplemented with 15N labelled wheat for a period of 2 days. The 15N excess was 295mg. 3 birds each were killed 3, 6, 12, 60 and 108 hours after administration of the last 15N dose. The present communication provides data on the N and 15N content of the bone skin, feathers and data on the 15N balance. On an average, 11% of the amount of 15N administered were found in medullar bones. A fairly uniform pattern of 15N labelling was observed at the different test points of the skin while the time pattern of 15N frequencies in the feathers was non-directional. 15N' balance showed that at all the 6 test point the range of error for the recovery rates was less than 3%. The present study substantiated the suitability of the stable N isotope for use in N metabolism trials.     

Microregional distributions of glucose, lactate, ATP and tissue pH in experimental tumours upon local hyperthermia and/or hyperglycaemia

Microregional distributions of glucose, lactate and ATP concentrations as well as tissue pH values were determined in subcutaneous rat tumours during normothermia and normoglycaemia, and upon local hyperthermia (HT) and/or hyperglycaemia (HG). Experiments were performed in order to investigate whether, and to what extent, these adjuvant therapeutic measures applied alone or in combination can modify the bioenergetic and metabolic status, parameters that are known to markedly influence the therapeutic response of tumours to heat. Local HT was performed in a saline bath (44 degrees C/2 h) and HG was induced by i.v. infusion of glucose for 2.5 h (blood glucose levels during heating: 35-40 mM). Immediately after treatment, the microregional distributions of glucose, lactate and ATP concentrations were assessed using quantitative bioluminescence and single-photon counting. In corresponding histological sections the fraction of tumour tissue with changes indicating cellular damage was determined. For comparison, global levels of glucose, lactate, ATP, ADP and AMP were measured using enzymatic assays or HPLC. Tumour tissue pH values were recorded immediately after treatment with miniaturised needle glass pH electrodes. Upon HT alone, the microregional glucose distribution remained unchanged. Lactate concentrations significantly increased, resulting in a pH drop of about 0.20 pH units. Mean ATP concentrations decreased without an obvious change in the shape of the distribution curve. The fraction of tumour tissue showing cellular damage increased from 18% (in control tumours) to 27%. Upon HG alone, mean glucose and lactate levels in the tumours increased. Glucose, lactate and pH distributions became broader. Lactate accumulation results in a severe tumour acidosis (mean pH = 6.22). Mean ATP concentrations marginally decreased despite a higher glucose availability, probably because of poorer ATP yield resulting from changes in metabolic channelling (Crabtree effect). The fraction of tumour tissue exhibiting cellular damage was 23%. Following the combined treatment (HT/HG), glucose and lactate levels, and tissue pH were similar to those seen upon HG alone. However, ATP concentrations were lowest under this condition. The variation of tumour ATP concentrations is substantially reduced with only a few tumour areas remaining with ATP levels of at least 0.6 mumol/g. The ATP depletion upon HT/HG is accompanied by a drastic increase in the fraction of tissue areas exhibiting cellular damage to 61%. It may therefore be concluded that only the combined treatment can deplete ATP to such an extent that a pronounced cytotoxic effect is achieved.