Therapeutic evaluation of compounds in the SCID-RA papillomavirus model

A previous study by Kreider (Kreider et al., 1979) indicated that rabbit skin, which had been transplanted to immunodeficient nude mice, could be successfully infected with cottontail rabbit papillomavirus (CRPV). We have extended this observation in developing a rodent model for evaluation of compounds for activity against the papillomaviruses. In this model (called the SCID-Ra model), rabbit ear skin is transplanted to the dorsum of SCID mice and allowed to heal for 3 weeks. Infection with CRPV by scarification leads to the growth of warty lesions within 2 3 weeks in >95% of the animals. Topical and/or systemic therapy can be initiated at various times post infection (PI). Weekly lesion scores are recorded and compounds are evaluated for their ability to suppress wart growth when compared to untreated control mice. Ribavirin, which has had a suppressive effect both in the clinic for the treatment of respiratory papillomatosis and on the growth of warts in the rabbit back model, was evaluated and showed significant anti-proliferative activity with oral dosing. Both antiviral and antiproliferative compounds including podophyllin and 5-fluorouracil, which have been used clinically for the treatment of human papillomavirus (HPV) infections, were evaluated in this model. The anti-mitotic compound, Navelbine (vinorelbine tartrate), which is used for the treatment of non-small cell lung carcinoma was evaluated in this system and showed significant inhibition of wart growth with somewhat less topical cytotoxicity when compared to podophyllotoxin.     

Comparative severity of respiratory lesions of sialodacryoadenitis virus and Sendai virus infections in LEW and F344 rats

In several chronic diseases, lesions are more severe in LEW rats than in F344 rats. To determine whether or not acute viral diseases also are more severe in LEW rats than in F344 rats, we inoculated 6-7-week-old LEW and F344 rats with 10(7.2) cell culture infective units of sialodacryoadenitis virus or 10(4.7) infective units of Sendai virus. Twenty-four rats of each strain were given each virus. Lesions in nasal passages, tracheas, intrapulmonary airways, and pulmonary alveoli in 6 or 12 rats inoculated with each virus were assessed by scoring 5, 10, and 14 days after inoculation. Both viruses caused typical patchy necrotizing rhinitis, tracheitis, bronchitis, and bronchiolitis, with multifocal pneumonitis, in rats of both strains. Mean lesion indices for LEW rats given sialodacryoadenitis virus were significantly different from those for F344 rats for nasal passages on days 10 (0.999 vs. 0.680) and 14 (0.736 vs. 0.278), bronchi on day 5 (0.479 vs. 0.361), and alveoli on day 5 (0.677 vs. 0.275). Lesion indices for LEW rats given Sendai virus were significantly different from those for F344 rats for nasal passages on days 10 (1.000 vs. 0.611) and 14 (0.778 vs. 0.583); trachea on day 10 (0.625 vs. 0.028); bronchi on days 5 (0.476 vs. 0.331), 10 (0.123 vs. 0.013), and 14 (0.038 vs. 0); and alveoli on days 5 (0.413 vs. 0.114) and 10 (0.185 vs. 0.020). Thus, at the tested doses, both viruses caused more severe respiratory tract lesions in LEW rats than in F344 rats.     

Generalized oscillator-strength calculations for some low-lying excited states of H2 using a high-accuracy configuration-interaction wave function

Replacement of Met31 by (N-Me)Nle in CCK8 or CCK4 has been shown to improve the affinity and selectivity for CCK-B receptors. In order to obtain molecules with enhanced bioavailability, two novel series of protected tetrapeptides of the general formula Boc-Trp30-X-Asp-Y33 have been developed. Introduction of (N-Me)Nle and the bulky, aromatic naphthylalaninamide (Nal-NH2) in positions X and Y, respectively, does not greatly modify the affinity for guinea pig brain CCK-B receptors. In contrast, incorporation of hindering N-methyl amino acids such as (N-Me)Phe, (N-Me)Phg, or (N-Me)Chg, but not their non-methylated counterparts, in position X induced a large decrease in affinity for the CCK-B binding sites. Among the various peptides synthesized, Boc-[(N-Me)Nle31,1Nal-NH2(33)]CCK4 (2) (KI = 2.8 nM), Boc-[Phg31,1Nal-NH2(33)]CCK4 (15) (KI = 14 nM), and Boc-[Phg31,1Nal-N(CH3)2(33)]CCK4 (17) (KI = 39 nM) displayed good affinities for brain CCK-B receptors and had good selectivity ratios. These pseudopeptides, in which the presence of unnatural and hydrophobic residues is expected to improve their penetration of the central nervous system, were shown to be very resistant to brain peptidases. Interestingly, whereas compounds 2 and 15 proved to be full agonists for rat hippocampal CCK-B receptors when measured in an electrophysiological assay, compound 17 behaved as a potent antagonist in the same test and displayed a good affinity in rat brain KI(CCK-B) = 51 nM as compared to the Merck antagonist L365,260,KI(CCK-B) = 12 nM. This illustrates a simple means to obtain CCK-B antagonists and suggests that the free, CONH2 group plays a critical role in the recognition of the agonist state of brain CCK-B receptors.     

Routine prenatal screening for congenital heart disease: what can be expected? A decision-analytic approach

OBJECTIVES: This study assessed the potential impact of fetal ultrasound screening on the number of newborns affected by cardiac anomalies. METHODS: A decision model was developed that included the prevalence and history of congenital heart disease, characteristics of ultrasound, risk of abortion, and attitude toward pregnancy termination. Probabilities were obtained with a literature survey; sensitivity analysis showed their influence on expected outcomes. RESULTS: Presently, screening programs may prevent the birth of approximately 1300 severely affected newborns per million second-trimester pregnancies. However, over 2000 terminations of pregnancy would be required, 750 of which would have ended in intrauterine death or spontaneous abortion. Further, 9900 false-positive screening results would occur, requiring referral. Only the sensitivity of routine screening and attitude toward termination of pregnancy appeared to influence the yield substantially. CONCLUSIONS: The impact of routine screening for congenital heart disease appeared relatively small. Further data may be required to fully assess the utility of prenatal screening.     

The likelihood of violent behaviour: Predictions, postdictions, and hindsight bias.

Studied the effects of variations in base rate (BR) information and temporal context on predictions of violence and hindsight bias (HB). 270 undergraduates estimated the likelihood of violent offenders committing another violent offense based upon fictitious case history information. Ss were given 1 of 2 population BRs of the likelihood of reoffending (30% or 70%) and a recidivism estimation question that was phrased either predictively, predictively with a given outcome of either recidivism or no recidivism, or postdictively. Although different offenders were perceived as differentially likely to reoffend, estimated likelihood of recidivism was affected by neither BR nor temporal phrasing of the estimation task. A 2nd study of 182 undergraduates, using shorter case histories, also found no BR effect. HB effects were weak and inconsistent in both studies. (French abstract) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Germicidin, an autoregulative germination inhibitor of Streptomyces viridochromogenes NRRL B-1551

During germination spores of Streptomyces viridochromogenes NRRL B-1551 excrete a compound, germicidin, which has an inhibitory effect on the germination of its own arthrospores at a concentration as low as 200 pM (40 pg/ml). At higher concentrations germicidin inhibits porcine Na+/K(+)-activated ATPase and retards the germination of the cress Lepidium sativum. Germicidin is the first known autoregulative inhibitor of spore germination in the genus Streptomyces and was isolated from the supernatant of germinated spores, but also from the supernatant of the submerged culture. Spectroscopic analysis and derivatization reactions revealed germicidin to be 6-(2-butyl)-3-ethyl-4-hydroxy-2-pyrone (C11H16O3). Crude isolates of germicidin from the supernatant of submerged culture, but not from the spores, contained a second, structurally very similar compound (C10H14O3), in which in contrast to germicidin a 2-propyl instead of the 2-butyl chain was bound to C-6 and which did not show any activity in the germination and ATPase assay. The germination assay was evaluated as a new screening model for specifically active compounds.     

MPC as a tool for sustainable development integrated policy assessment

A recent stochastic and multiobjective formulation based on static open-loop optimization has laid the foundations of a quantitative approach to sustainable development policy assessment. Here, the connections between such an approach and model predictive control are explored, and a reformulation that introduces dynamics and addresses closed loop performance and stability is proposed. The approach has wide applicability but it is hoped that it will provide sustainable development practitioners in particular with new insights.     

Frequency-dependence of myocardial energetics in failing human myocardium as quantified by a new method for the measurement of oxygen consumption in muscle strip preparations

Diastolic dysfunction at high heart rates may be associated with increased myocardial energy consumption. Frequency-dependent changes of isometric force and oxygen consumption (MVO2) were investigated in strip preparations from endstage failing human hearts exhibiting various degrees of diastolic dysfunction. MVO2 was determined by a new method which was validated. When stimulation rate was increased from 40 to 200 min-1 (n=7), developed force decreased from 16.5+/-4.3 to 7.9+/-2.9 mN/mm2 (P<0.01), diastolic force increased from 15.9+/-3.2 to 22.0+/-3.0 mN/mm2 (P<0.01), and total MVO2 increased from 2.6+/-0.6 to 4.7+/-0.9 ml/min/100 g (P<0.025). Resting MVO2 and resting force were 1.8+/-0.4 ml/min/100 g and 15.9+/-3.0 mN/mm2, respectively. After addition of 30 mm 2,3-butanedione monoxime (BDM) to inhibit crossbridges, resting MVO2 and resting force decreased by 46% (P<0.05) and 15% (P<0.01), respectively, indicating the presence of active force generation in unstimulated failing human myocardium. In each muscle preparation, there was a significant correlation between force-time integral (FTI) and total MVO2 (r=0.96+/-0.01). The strength of these correlations did not vary with the contribution of diastolic FTI to total FTI. The ratio of activity related MVO2 to developed FTI, an inverse index of the economy of contraction, increased depending on the rise of diastolic FTI at higher stimulation rates. In conclusion, in failing human myocardium, diastolic force development is occurring at the same energy expenditure as systolic force generation. Therefore, in muscle preparations with disturbed diastolic function economy of contraction decreases with higher stimulation rates, depending on the rise of diastolic force.