Electroporation-mediated delivery of a naked DNA plasmid expressing VEGF to the porcine heart enhances protein expression.

Gene therapy is an attractive method for the treatment of cardiovascular disease. However, using current strategies, induction of gene expression at therapeutic levels is often inefficient. In this study, we show a novel electroporation (EP) method to enhance the delivery of a plasmid expressing an angiogenic growth factor (vascular endothelial growth factor, VEGF), which is a molecule previously documented to stimulate revascularization in coronary artery disease. DNA expression plasmids were delivered in vivo to the porcine heart with or without coadministered EP to determine the potential effect of electrically mediated delivery. The results showed that plasmid delivery through EP significantly increased cardiac expression of VEGF compared with injection of plasmid alone. This is the first report showing successful intracardiac delivery, through in vivo EP, of a protein expressing plasmid in a large animal.

Well-being at the end of life: Part 1. A research agenda for psychosocial and spiritual aspects of care from the patient's perspective.

This article reviews the scientific literature concerning psychosocial and spiritual aspects of palliative care for the patient with cancer. It discusses 4 separate areas: the continuum of care, communication, spiritual and psychological issues, and psychotherapeutic and behavioural management of physical symptoms. Most of the research could be classified as fundamental according to the Cancer Control Framework of the National Cancer Institute of Canada. In some areas, even fundamental research was lacking. There is a need for clearer and more relevant definitions of the desired outcomes of interventions and also for the development of appropriate quantitative and qualitative methods. We must determine which interventions can be initiated earlier in the disease trajectory and can provide benefit at the palliative phase. Given the burden of suffering that palliative care aims to address, relatively little research in this area has been conducted.

Clearance of recombinant tissue factor pathway inhibitor (TFPI) in rabbits.

The pharmacokinetics of recombinant tissue factor pathway inhibitor (TFPI) after an intravenous bolus injection was studied in rabbits. Clearance of TFPI was followed by measurement of the radioactivity of the 125I-labelled compound in the whole plasma or the trichloroacetic acid precipitate and by quantitation of the functional TFPI activity of the unlabelled compound using a tissue factor-induced coagulation assay. When iodinated TFPI was used, the ratios of the trichloroacetic acid precipitable counts vs. that of the whole plasma was about 1 in the first 10 min after TFPI injection, but this ratio gradually decreased to less than 0.5 after 2 h. This result suggested that the iodinated TFPI in the plasma was partially degraded after prolonged circulation in the animal. When unlabelled TFPI was used, the clearance of TFPI activity from the plasma exhibited bi-exponential elimination kinetics with a rapid alpha phase half-life (t1/2 alpha) of 2.3 min, and a terminal beta phase half-life (t1/2 beta) of 79 min. The plasma clearance was 4.2 ml kg-1 min-1. The tissue distribution of intravenously administered 125I-TFPI in the rabbit was studied using whole-body autoradiography. At 3 min after dosing, significant levels of TFPI were apparent in the liver, kidney, and other highly blood perfused tissues. Significant levels of 125I-TFPI-derived radioactivity were also apparent in the liver and kidney at 30 min after intravenous administration. The localization within the liver demonstrated a mottled appearance, suggesting regions of higher uptake within the liver. In the kidney, the outer cortex consistently revealed the highest activity.

Feeding studies in rats with mineral hydrocarbon food grade white oils.

This investigation compared the effects of feeding rats diets containing food grade white oil processed by either conventional oleum treatment or the more modern method of catalytic hydrogenation. In two separate experiments, male or female Fischer-344 rats were given free access for 90 days to diets containing 0, 10, 100, 500, 5,000, 10,000, or 20,000 ppm of either oleum-treated white oil (OTWO) or hydrotreated white oil (HTWO). There were no mortalities and no adverse clinical signs associated with feeding either white oil. Treatment-related effects evidenced by hematological, clinical chemical, and pathological changes were generally dose-related and more marked in female than in male rats, and the OTWO caused a greater pathological response than the HTWO. Tissue residues of saturated hydrocarbons were up to 5.2 times higher in female rats than in males. Rats fed 5,000 ppm or more of either white oil showed dose-related alterations in several hematological and clinical chemistry variates associated mainly with hepatic damage or functional alteration. At necropsy, mesenteric lymph nodes were enlarged, and increases in weight of liver, kidney, and spleen were significant. Microscopic changes were characterized by multifocal lipogranulomata in mesenteric lymph node and liver. No changes were observed in rats fed OTWO or HTWO for 90 days at dietary concentrations of 10 or 100 ppm, equivalent to a minimum intake of 0.65 and 6.4 mg/kg/day, respectively. Differences in degree of pathological response associated with each oil may have been due to their differences in specification rather than processing method.

Human dose-excretion studies with the pyrethroid insecticide, cypermethrin.

1. An analytical method for monitoring human exposure to cypermethrin has been developed, based on the detection of the free and conjugated forms of the urinary metabolite, the cyclopropanecarboxylic acid. 2. Four male subjects were given a single oral dose, ranging from 0.25 mg to 1.5 mg, of a 1:1 cis/trans mixture of cypermethrin, and urine was monitored for the free and conjugated cyclopropanecarboxylic acid. Urinary excretion of the individual metabolites (cis and trans isomers) was similar for the different dosages. Subjects excreted, on average, 78% of the trans isomer dose, and 49% of the cis isomer dose respectively in 24 h. 3. Thus, as in other mammals, ester cleavage and elimination of the cis and trans cyclopropanecarboxylic acid moieties in the free and conjugated form is a major route of metabolism of cypermethrin in man.

Effect of vocal disguise on judgments of speakers' sex and race.

To determine the effect of speakers' attempts to disguise their voices on listeners' accuracy in judgments of speakers' sex and race, 26 speakers, 13 women and 13 men, recorded six sentences under three conditions: (a) in a normal manner, (b) in a manner in which they attempted to sound like a member of the opposite sex, and (c) in a manner in which they attempted to sound like a member of the black race. Three master tapes were constructed, one for each of the three conditions. A total of 40 judges, 20 in an experiment on sex identification and 20 in one on race identification, participated in two sessions, one for each of two tapes (control and disguise) in each experiment. In each session they were asked to judge the sex or race of the speaker of each sentence and, using a seven-point confidence rating scale, to indicate the over-all confidence in their judgments at the end of each session. Analysis indicated that, although listeners' accuracy for sex and race identification was greater under the control than disguised conditions for the majority of speakers, the differences between the two conditions were relatively small. Implications of these findings and suggestions for future research are discussed.

The metabolism of 3-chloro-4-fluoro-aniline in dog and rat.

1. 3-Chloro-4-fluorol[14C]aniline, orally administered to a female dog (0.135 mg/kg), was eliminated in the urine as 2-amino-4-chloro-5-fluorophenyl sulphate (83% in 48 h). 2. When 3-chloro-4-fluoro[14C]aniline was administered orally to male rats (ca 2.3 mg/kg), the 0-24 h urine contained 2-amino-4-chloro-5-fluorophenyl sulphate (52% of the aniline dosed), N-(5-chloro-4-fluoro-2-hydroxyphenyl)acetamide (13%) and an unidentified metabolite (16%). 3. 2-Amino-4-chloro-5-fluorophenyl sulphate was identified after extraction as salts by proton and fluorine-19 magnetic resonance spectroscopy. N-(5-Chloro-4-fluoro-2-hydroxyphenyl)acetamide was identified by mass spectrometry and proton magnetic resonance spectroscopy.

Detoxication and bioactivation of endrin in the rat.

1. Rats exhibit a sex difference in the rate of metabolism of endrin. 2. The major metabolite in both sexes is anti-12-hydroxyendrin which is excreted via the bile as the glucuronide. Male rats produce the metabolite at a higher rate than do females. 3. trans-4,5-Dihydroisodrin-4,5-diol is a minor metabolite. A mechanism for its formation is discussed. 4. There is a sex difference in the production and excretion of 12-ketoendrin which is observed as a urinary metabolite in male rat; the major urinary metabolite in female rats is anti-12-hydroxyendrin O-sulphate. 5. syn-12-Hydroxyendrin was not detected but may be an intermediate in the formation of 12-ketoendrin. 6. The formation of 12-ketoendrin is related to the acute toxicity of endrin.