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Using 2D smoothed particle hydrodynamics, we investigate the distribution of wait times between strong shocks in a turbulent, self-gravitating accretion disc. We show that the resulting distributions do not depend strongly on the cooling time or resolution of the disc and that they are consistent with the predictions of earlier work. We use the distribution of wait times between shocks to estimate the likelihood of stochastic fragmentation by gradual contraction of shear-resistant clumps on the cooling time-scale. We conclude that the stochastic fragmentation mechanism cannot change the radius at which fragmentation is possible by more than ~20 per cent, restricting direct gravitational collapse as a mechanism for giant planet formation to the outer regions of protoplanetary discs. [ABSTRACT FROM AUTHOR]

The use of genetically engineered, replication-selective viruses to treat cancer is being realized with viruses such as ONYX-015, a human adenovirus that selectively destroys p53 mutant cancer cells. To enhance further the clinical efficacy of ONYX-015 and viruses like it, we have developed a novel gene delivery system for replicating adenoviruses. This system has two unique features. First, it uses the endogenous adenoviral gene expression machinery (promoter, splicing, polyadenylation) to drive transgene expression. Second, a single region or gene in the multi-gene E3 transcription unit is selectively substituted for by the therapeutic transgene(s). Analyzing various transgene substitutions for the 6.7 K/gp19 K region of E3, we demonstrate the following: (1) transgene expression in this system is predictable and mimics the substituted endogenous gene expression pattern, (2) expression of surrounding E3 genes can be retained, (3) the insertion site choice can effect both the transgene expression level and the viral life cycle, and, (4) expression levels from this system are superior to those generated from a replication-defective virus using the HCMV enhancer-promoter and this is dependent on viral DNA replication. This unique methodology has broad application to the rapidly evolving field of replicating virus-based therapies. Gene Therapy (2001) 8, 1123–1131. [ABSTRACT FROM AUTHOR]

Infection-induced hyperlipidemia develops due to a combination of factors, one of which is decreased clearance of lipids from the bloodstream due to depressed synthesis of lipoprotein lipase (LPL). Recently, the peroxisome proliferator activated receptors (PPARs) have been shown to be important in the regulation of LPL, particularly PPARgamma. PPARgamma and its heterodimerization partner, RXR alpha have been shown to be transcriptional activators of LPL in co-transfection analysis. Therefore, we hypothesized that the decrease in LPL expression during endotoxemia may be a result of depressed PPARgamma expression. In these studies, we examined the effect of endotoxin or its proximal mediator, tumor necrosis factor (TNF), on the expression of PPARgamma in white (WAT) and brown adipose tissue (BAT) in CD-1 mice. We report that treatment with endotoxin, but not TNF, transiently decreased PPARgamma mRNA levels 4 hr after treatment. However, endotoxin or TNF treatment decreased PPARgamma protein levels after 18 hr, which was at a time when LPL mRNA levels were also depressed. These data suggest that decreased PPARgamma expression following endotoxin or TNF treatment may contribute to the hyperlipidemia due to decreased expression of LPL, which would impair triglyceride clearance.

Mammary secretions (n = 34 cows) and mammary phagocytes (n = 18 cows) were collected throughout the nonlactating (dry) period to determine changes in intramammary phagocytic defense mechanisms. Mammary secretions were evaluated for their ability to support phagocytosis of Staphylococcus aureus by neutrophils from donor cows and mammary phagocytes for phagocytic and chemiluminescence activity. Ability of secretions to support phagocytosis decreased with advancing length of the dry period. This effect was more pronounced when dry cow secretions constituted 50% of the phagocytic mixture. Phagocytic activity of mammary phagocytes decreased with advancing dry period when autologous secretion was used in the incubation mixture. With homologous secretion, the percentage of phagocytosis increased 5 to 6 d after drying off compared with before drying off and then gradually decreased throughout the remainder of the dry period. Chemiluminescence activity (log10 counts per minute) of mammary phagocytes was lower during the dry period and decreased with advancing dry period. Results indicated diminishing ability of secretions to support phagocytosis and diminished phagocytic and bactericidal mechanisms during the dry period.

Eighteen Holstein cows free of intramammary infection were sampled during dry period to measure changes in total SCC, differential cell counts, and N-acetyl-beta-D-glucosaminidase activity of milk or dry secretion. The design was to sample prior to and at drying off, two or more times during wk 1 of dry period, at 14 and 21 d of dry period, and after calving; 7 cows were sampled rotationally by quarters at 7, 14, and 21 d to avoid altering normal processes by repeated sampling. Total SCC of secretions declined just after drying off, increased to a peak of 6.593 (log10 scale) at 2 wk, and then declined slightly at 3 wk. Percentage of neutrophils rose from 33.3 at drying off to 83.8 at 1 wk and declined to 59.2 at 3 wk. Lymphocyte percentage declined in wk 1 of dry period but increased during wk 2 and 3. Activity of N-acetyl-beta-D-glucosaminidase in secretion rose throughout the first 3 wk of dry period.

Forty-six patients with Zollinger-Ellison syndrome were studied prospectively to determine a safe and effective method and criterion for controlling gastric acid hypersecretion during periods when oral antisecretory agents could not be used. In each patient it was possible to reduce acid secretion to less than or equal to 10 mEq/h after an i.v. bolus of 150 or 300 mg of cimetidine and a stepwise titration of cimetidine given by continuous infusion. The mean dose given by i.v. infusion was 2.9 mg/kg body wt.h but there was a wide range (0.5-7.0 mg/kg body wt.h) and the minimal dose had to be determined individually for each patient. The minimal i.v. cimetidine dose did not correlate with basal or maximal acid output or fasting gastrin concentration, but correlated closely with either the previous oral dose of cimetidine (r = 0.96, p less than 0.001) or the previous oral dose of ranitidine or famotidine (r = 0.95, p less than 0.001). To study the efficacy and safety of an i.v. infusion of cimetidine, 34 patients undergoing surgery were maintained on i.v. cimetidine for a mean of 12 days (range 1-83 days). One-half of the patients did not require dose adjustment, whereas the remainder required an average of 2 adjustments, usually in the first 3 postoperative days. No patient developed complications attributable to gastric acid hypersecretion in the postoperative period, and there was no detectable neurologic, hematologic, or hepatic toxicity. This study demonstrates that a continuous i.v. infusion of cimetidine adequately inhibits gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. However, high doses were frequently required, the dose had to be determined in a stepwise fashion individually for each patient, and the i.v. dose correlated with the previous oral dose. Reducing acid secretion to less than or equal to 10 mEq/h was a safe criterion during surgery and continuous i.v. cimetidine was safe and effective in achieving this degree of control for up to 83 days.

Plasmodium hermani was experimentally transmitted from domestic turkey poults (Meleagris gallopavo) to pen-reared bobwhites (Colinus virginianus) and then from these bobwhites back to domestic turkey poults. Transmission was achieved by Culex nigripalpus both by bites of the mosquito and by intraperitoneal injection of sporozoites. All of the 23 bobwhites and the 13 turkeys exposed to sporozoites became infected. These results indicate that the bobwhite might be a reservoir host for this malaria of wild turkeys in nature.

Culex nigripalpus experimentally transmitted Plasmodium hermani, a plasmodium of wild turkeys (Meleagris gallopavo) in Florida. The mosquitoes were infected by feeding upon blood induced parasitemias in domestic turkey poults. The resulting sporozoites, transmitted by either mosquito bites or injection, produced malaria infections in domestic poults.

Of 174 medical graduates who had undertaken residency training in pediatrics at the Health Centre for Children, Vancouver between 1958 and 1972, 156 replied to a questionnaire designed to determine their present activity. Excluding those still in training 58.4% are currently practising pediatrics, 28% are in family practice and 12.8% are in other areas of professional activity; 49% obtained a specialty degree in pediatrics and 5.4% obtained certification of the Royal College of Physicians and Surgeons of Canada in another specialty. Of the total, 69% have remaind in Canada; of the Canadian graduates 83% have remained in this country, compared with 63.8% of graduates from other countries. Estimation of pediatric manpower requirements should take into account the anticipated increase in population, the pediatrician attrition rate, the contribution one province may provide for the rest of the country, and the fact that only approximately 60% of pediatric trainees will ultimately practise this specialty.

Dose-interval AUC and clearance of theophylline at steady-state were determined in healthy male subjects in each of three age groups (18-35, 36-54 and 55-70 years old). Mean AUC in the oldest group was significantly higher than in the youngest and clearance in both the middle and oldest groups was significantly lower than in the youngest. Though clearance was significantly correlated with age, age alone accounted for only 31% of the variability in clearance.

The authors present the results of a study carried out to determine the efficacy of chloroquine- and pyrimethamine-salt mixtures as a suppressive against sporozoite-induced vivax malaria (Chesson strain). The test subjects used in this study were volunteers of military age in the US Penitentiary at Atlanta, Ga. The subjects chosen were all in good physical condition and had no previous history of malaria.Both drug-salt mixtures were entirely acceptable to the volunteers, were indistinguishable in taste and appearance from ordinary salt, and remained stable under the conditions of food preparation. The weekly dosage of the drugs (300 mg of chloroquine base or 25 mg of pyrimethamine per 50 g of salt) had in each case been adjusted to the average salt consumption. Suppression of malaria was found to be complete throughout the salt-drug regimen and for 28-43 days thereafter, even though the subjects were exposed to repeated heavy doses of sporozoites. In contrast, the control subjects, exposed to the same infective doses, all exhibited parasitaemia 13-15 days after exposure.The procedures for preparing the drug-salt mixtures are described in detail and a simple method for determining the salt consumption by measurement of the urinary chloride excretion is outlined.