5-Fluorouracil (5-FU) continuous intravenous infusion compared with bolus administration. Final results of a randomised trial in metastatic colorectal cancer

The aim of this Phase III, balanced randomised trial was to compare continuous intravenous infusion (CVI) of 5-FU with bolus (B) administration for metastatic colorectal cancer (CRC). One hundred and fifty-five non-pretreated patients were randomised to receive CVI 5-FU at a dose of 750 mg/m2/day (d), 7 d every 21 d (n = 77), or bolus 5-FU 500 mg/m2/d x 5 d every 28 d (n = 78). Incremental dose escalation at 50 mg per step was recommended in the absence of toxicity. All the patients had measurable metastatic disease (M), particularly, liver and a good performance status (WHO grade 0-1). Dose intensity was significantly higher in CVI than in the bolus group: 1369 mg/m2/week versus 558 mg/m2/week (P = 0.0001). Grade II-IV stomatitis was more frequent in the CVI group (31% versus 9%; P < 0.0001) as was hand and foot syndrome (14% versus 3%; P < 0.001). Diarrhoea (22% versus 12%) and grade III granulocytopenia (2% versus 6%) were comparable. Responses were more frequent in the CVI (26%) than in the bolus group (13%) (P < 0.04); progression-free survival was higher for the CVI group (P = 0.04), but there was no statistical difference in overall survival (median: 10 months (m) compared to 9 m), and 1 year survival (SD) 42% (6%) versus 40% (6%). In the multivariate analysis, survival was better for patients with a good PS, well-differentiated adenocarcinomas and a primary tumour without serosal extension. In conclusion, with a higher dose intensity, CVI 5-FU improved tumour control, but not overall survival.     

A vibrating-tube densimeter for fluids at high pressures and temperatures

A vibrating U-tube apparatus has been developed for determining the densities of pure fluids and fluid mixtures at 10-200 MPa and 323-773 K. Measured parameters areP,T, andr (period of vibration). Fluids are injected into the U-tube at constantP andT. Three or more reference fluids are used to calibrate the response of the instrument. Fluid mixtures are produced by pumping pure fluids into T-junctions on the upstream side of the U-tube using high accuracy syringe pumps. An automated syringe pump is used to maintainP at setpoint ±0.01 MPa.T is controlled to ±0.01 K using a closed-loop, electronic signal amplification/feedback system. For mixtures, a statistically significant number of measurements of r are obtained to account for the effects of small heterogeneities in fluid composition (generally <0.005X;). Typically, density data for 15 fluids can be obtained in a 6- to 8-h period. Considering all of the potential sources of error in the experimentation, conservative estimates of uncertainty are as follows:P, ±0.02 MPa;T, ±0.05 K;p (pure fluids), ±0.0005g.cm^–3; andp (fluid mixtures), ±0.0005-0.0010g-cm^–3.Paper presented at the Twelfth Symposium on Thermophysical Properties, June 19–24, 1994, Boulder, Colorado, U.S.A.     

Changes of the corneal endothelium after ultraviolet-B exposure in previously photokeratectomized eyes

The photorefractive effect of excimer lasers is based on an interaction between the 193-nm ultraviolet-C laser beam and the stromal chromophore molecules. Recently, in some patients an increase of subepithelial haze and a regression of refractive effect has been observed following suntanning (UV-B exposure). The aim of the study was to find out the possible endothelial damage caused by photoablation with increasing depth and the effect of subsequent UV-B exposure on previously photokeratactomized eyes. Altogether 12 chinchilla rabbits were treated. Four animals received a -5.0 D PRK; four animals a -15.0 D PRK and four animals a -30.0 D PRK treatment. The endothelial average number, size and variation were determined two weeks post-PRK. Three weeks following PRK, a half of the animals received a 1 J/cm2 ultraviolet-B radiation in a constant dermatological UV-chamber. The endothelial morphology was measured the same way with automated specular microscopy two weeks after UV-B irradiation. After PRK treatment there was no statistically demonstrable change in endothelial morphology. On the other hand, after UV-B radiation all eyes showed a decrease in endothelial number and an increase in size and variation. The ratio of hexagonality decreased, and endothelial rosette formation appeared. The early morphological changes resembled the physiological aging changes. Conditions (deep stromal photoablation, cumulative effect of suntanning or solarium treatments) may exaggerate the physiological aging processes leading to subsequent pleomorphism, polymegatism and cell loss. This may accelerate corneal dysfunction.     

A monolithically integrated optical differential amplifier forapplications in smart pixel arrays

A cascadable, optical differential amplifier with an active output is realized in AlGaAs-GaAs by the monolithic integration of three devices: A photodiode (PD), a light-emitting diode (LED) and a combination of a photodiode and a junction field-effect transistor (PINFET). A minimum optical switching power of 15 pW, an optical gain of more than 10⁶, a contrast ratio greater than 1000 and an optical output power of 17 μW are obtained. For a contrast ratio of 10, a switching energy of 2 pJ is required, resulting in a unity gain bandwidth of 4.2 MHz     

The synthesis of symmetrical and unsymmetrical P1/P1' cyclic ureas as HIV protease inhibitors

Cyclic urea SD146, a potent HIV protease inhibitor bearing a flat resistance profile, possessed poor solubility and bioavailability, which precluded further development of the compound. In an effort to improve upon the pharmacokinetic profile of the compound, several analogs modified at the P1/P1' residues were prepared and evaluated. Several of those compounds displayed significant improvement of physical properties.     

Infection and stage conversion during murine pulmonary toxoplasmosis: a study with three different strains of Toxoplasma gondii

OBJECTIVE: To investigate whether intravenously administered liposomal alpha-tocopherol can protect the lung from the injurious action of Escherichia coli lipopolysaccharide (LPS). DESIGN: Prospective, randomized animal study. SETTING: Government research laboratory. SUBJECTS: Twenty adult male Sprague-Dawley rats. INTERVENTIONS: Animals were intravenously pretreated with alpha-tocopherol liposomes (20 mg alpha-tocopherol/kg body weight), plain liposomes, or saline. Twenty-four hours later, pretreated animals were challenged with an intravenous injection of LPS (E. coli 0111:B4, 1 mg/kg body weight), and killed 2 hrs after LPS challenge. MEASUREMENTS AND MAIN RESULTS: Challenge of saline-pretreated animals with LPS resulted in lung injuries as evidenced by an increase in wet lung weight and a reduction in pulmonary angiotensin converting enzyme (25%) and alkaline phosphatase (28%), injury markers of lung endothelial and epithelial type II cells, respectively. Also, LPS administration resulted in an increase in pulmonary myeloperoxidase and protease activities, indicative of a neutrophilic inflammatory response. Pretreatment of animals with liposomal alpha-tocopherol significantly attenuated the LPS-induced edematous lung weight response, and reduced the extent of injuries to the pulmonary endothelial and epithelial cells, demonstrated by a significantly smaller reduction in the corresponding enzyme marker activities. CONCLUSION: These results suggest that augmentation of the pulmonary antioxidant status can ameliorate LPS-induced lung injuries mediated by oxidative stress mechanisms.     

Characterisation of the adsorption sites of hydrogen on Pt/C fuel cell catalysts

A key component of a hydrogen fuel cell is a catalyst to dissociate dihydrogen to hydrogen atoms. In the present study, the adsorption of hydrogen on Pt/C fuel cell catalysts has been investigated by inelastic neutron scattering spectroscopy.

Monitoring a clean Pt(50%)/C catalyst with low energy neutron spectroscopy, after exposure to dihydrogen at 20 K, as it was heated to room temperature, showed three distinct temperature regimes: (i) a decrease in intensity from 10 to 60 K, (ii) a rise to a maximum between 60 and 120 K and then (iii) a slow fall-off towards room temperature. We assign the three regions as: (i) desorption of physisorbed dihydrogen, (ii) dissociation of dihydrogen to give an adsorbed layer and (iii) damping of the response by an increasing Debye–Waller factor.

The vibrational INS spectra of a series of Pt/C catalysts prepared under varying conditions were similar indicating that the same types of site are common to all the catalysts, although the relative proportions of each site are sample dependent. Features at 520, 950 and part of the intensity at 1300 cm⁻¹ are assigned to hydrogen on (1 1 1) faces, in good agreement with single crystal data. The mode at 640 cm⁻¹ is assigned as the doubly degenerate asymmetric stretch of Pt(1 0 0) faces with the symmetric stretch near 550 cm⁻¹.

We assign the bending mode of the on-top site to the feature at 470 cm⁻¹. The Pt–H stretch mode was observed at 2079 cm⁻¹. This is a significant result: this is the first time that hydrogen on the on-top sites has been observed on nanosized platinum particles supported on high surface area carbon black. The width of the INS peak is surprisingly large and may give additional information on the type and relative proportions of the crystallographic faces present on the catalyst particles.     

Forced intercalation probes (FIT Probes): thiazole orange as a fluorescent base in peptide nucleic acids for homogeneous single-nucleotide-polymorphism detection

Fluorescent base analogues in DNA are versatile probes of nucleic acid-nucleic acid and nucleic acid-protein interactions. New peptide nucleic acid (PNA) based probes are described in which the intercalator dye thiazole orange (TO) serves as a base surrogate. The investigation of six TO derivatives revealed that the linker length and the conjugation site decided whether a base surrogate conveys sequence-selective DNA binding and whether fluorescence is increased or decreased upon single-mismatched hybridization. One TO derivative conferred universal PNA-DNA base pairing while maintaining duplex stability and hybridization selectivity. TO fluorescence increased up to 26-fold upon hybridization. In contrast to most other probes, in which fluorescence is invariant once hybridization had occurred, the emission of TO-containing PNA probes is attenuated when forced to intercalate next to a mismatched base pair. The specificity of DNA detection is therefore not limited by the selectivity of probe-target binding and a DNA target can be distinguished from its single-base mutant under nonstringent hybridization conditions. This property should be of advantage for real-time quantitative PCR and nucleic acid detection within living cells.