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Background: Electronic nicotine delivery systems (ENDS, e-cigarettes) are increasingly used for the self-administration of nicotine by various human populations, including previously nonsmoking adolescents. Studies in preclinical models are necessary to evaluate health impacts of ENDS including the development of nicotine addiction, effects of ENDS vehicles, flavorants and co-administered psychoactive substances such as Δ 9-tetrahydrocannabinol (THC). This study was conducted to validate a rat model useful for the study of nicotine effects delivered by inhalation of vapor created by ENDS. Methods: Male Sprague-Dawley rats (N=8) were prepared with radio telemetry devices for the reporting of temperature and activity. Experiments subjected rats to inhalation of vapor generated by an electronic nicotine delivery system (ENDS) adapted for rodents. Inhalation conditions included vapor generated by the propylene glycol (PG) vehicle, Nicotine (1, 10, 30 mg/mL in the PG) and THC (12.5, 25 mg/mL). Results: Nicotine inhalation increased spontaneous locomotion and decreased body temperature of rats. Pretreatment with the nicotinic cholinergic receptor antagonist mecamylamine (2 mg/kg, i.p.) prevented stimulant effects of nicotine vapor inhalation and attenuated the hypothermic response. Combined inhalation of nicotine and THC resulted in apparently independent effects which were either additive (hypothermia) or opposed (activity). Conclusions: These studies provide evidence that ENDS delivery of nicotine via inhalation results in nicotine-typical effects on spontaneous locomotion and thermoregulation in male rats. Effects were blocked by a nicotinic antagonist, demonstrating mechanistic specificity. This system will therefore support additional studies of the contribution of atomizer/wick design, vehicle constituents and/or flavorants to the effects of nicotine administered by ENDS.

Combined, published reports of the effect of systemic corticosteroids on the course of bronchiolitis suggest a statistically significant improvement in clinical symptoms, LOS, and DOS.

Twin data can provide valuable insight into the relationship between the stages of phenomena such as disease or substance abuse. Initiation of substance use may be caused by factors that are the same as, partially shared with, or completely independent of those that cause progression from use to abuse. Comparison of rates of progression among the cotwins of twins who do vs. do not initiate provides indirect information about the relationship between initiation and progression. Existing models for this relationship have been difficult to extend because they are usually expressed in terms of explicit integrals. In this paper, the problem is overcome by regarding the analysis of twin data on initiation and progression as a special case of missing data, in which individuals who do not initiate are regarded as having missing data on progression measures. Using the general framework for the analysis of ordinal data with missing values available in Mx makes extensions that include other variables much easier. The effects of continuous covariates such as age on initiation and progression becomes simple. Also facilitated are the examination of initiation and progression in two or more substances, and transition models with two or more steps. The methods are illustrated with data on the effects of cohort on liability to cannabis use and abuse, bivariate analysis of tobacco use and dependence and cannabis use and abuse, and the relationships between initiation of smoking, regular smoking and nicotine dependence. Other suitable applications include the relationship between symptoms and diagnosis, such as fears and the progression to phobia.

Pediatric valganciclovir dosing recommendations have not been extensively validated for prevention or treatment for CMV infection. As such, we performed a pharmacokinetic study to compare different valganciclovir dosing regimens and the potential benefits of individualized dose adjustments in children following organ transplantation. Ganciclovir AUCs were calculated from four plasma drug levels in pediatric SOT recipients aged six months through three yr receiving valganciclovir suspension by mouth. Of the 28 ganciclovir AUC calculations performed, 11 (39%) were outside the therapeutic target range of 40-60 mcg h/L leading to a valganciclovir dose adjustment. Current manufacturer-recommended dosing based on BSA and CrCl was estimated to result in therapeutic AUCs in fewer patients than the simple weight-based formula used in our institution (4 vs. 13; p = 0.017). An AUC calculation using only the two- and five-h measurements was strongly correlated with the AUC using all four time measurements (R(2) = 0.846; p < 0.001). A simple weight-based dosing approach gives a higher probability for therapeutic AUCs compared to the manufacturer-recommended dosing in pediatric transplant patients aged six months through three yr with normal renal function. An AUC calculated using two sample times might allow for fewer blood draws in the future.

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BackgroundEarly screening for prostate cancer (PCA) remains controversial because of overdiagnosis and overtreatment of clinically insignificant cancers. Even though a number of diagnostic tests have been developed to improve on PSA testing, there remains a need for a more informative non-invasive test for PCA. The objective of this study is to identify a panel of DNA methylation markers suitable for a non-invasive diagnostic test from urine DNA collected following a digital rectal exam (DRE) and/or from first morning void (FV). A secondary objective is to determine if the cumulative methylation is indicative of biopsy findings.MethodsDRE and FV urine samples were prospectively collected from 94 patients and analyzed using 24 methylation-specific quantitative PCR assays derived from 19 CpG islands. The methylation of individual markers and various combinations of markers was compared to biopsy results. A methylation threshold for cancer classification was determined using a target specificity of 70%. The average methylation and the number of positive markers were also compared to the result of the biopsy, and the area under the receiver operating characteristic curves (AUCs) were calculated.ResultsMethylation of all 19 markers was detected in FV and DRE DNAs. Combining the methylation of two or more markers improved on individual marker results. Using 6of19 methylated markers as the threshold for cancer classification yielded a specificity of 71% (95% CI, 0.57–0.86) from both DRE and FV and a sensitivity of 89% (95% CI, 0.79–0.97) from DRE and 94% (95% CI, 0.84–1.0) from FV. The negative predictive value at the 6of19 threshold was ≥ 90 for both DNA types.ConclusionsPCA-specific methylation was detected in both FV and DRE DNA. There was no significant difference in diagnostic accuracy at the 6of19 threshold between DRE and FV urine DNA. The results support the development of a non-invasive diagnostic test to reduce unnecessary biopsies in men with elevated PSA. The test can also provide patients with personalized recommendations based on their own methylation profile.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0524-x) contains supplementary material, which is available to authorized users.