The present study sought to integrate convergent lines of research on the associations among the dopamine D4 receptor (DRD4) gene, novelty seeking, and drinking behaviors with the overall goal of elucidating genetic influences on problematic drinking in young adulthood. Specifically, this study tested a model in which novelty seeking mediated the relationship between DRD4 VNTR genotype and problematic alcohol use. Participants (N = 90, 40 females) were heavy drinking college students. Analyses using a Structural Equation-Modeling (SEM) framework suggested that the significant direct path between DRD4 VNTR genotype and problematic alcohol use was reduced to a trend level in the context of a model that included novelty seeking as a mediator, thereby suggesting that the effects of DRD4 VNTR genotype on problematic alcohol use among heavy drinking young adults were partially mediated by novelty seeking. Cross-group comparisons indicated that the relationships among the model variables were not significantly different in models for men versus women. These results extend recent findings of the association between this polymorphism of the DRD4 receptor gene, problematic alcohol use, and novelty seeking. These findings may also help elucidate the specific pathways of risk associated with genetic influences on alcohol use and abuse phenotypes.

The reasons why people smoke are varied, but research has demonstrated that genetic influences on various aspects of nicotine addiction are a major factor. There also is a strong genetic influence on measures of nicotine sensitivity in mice. Despite the established contribution of genetics to nicotine sensitivity in mice and humans, no naturally occurring genetic variation has been identified that demonstrably alters sensitivity to nicotine in either species. However, one genetic variant has been implicated in altering nicotine sensitivity in mice is a T529A polymorphism in Chrna4, the gene that encodes the nicotinic receptor (nAChR) α4 subunit. The Chrna4 T529A polymorphism leads to a threonine to alanine substitution at position 529 of the α4 subunit. To more definitively address whether the Chrna4 T529A polymorphism does, in fact, influence sensitivity to nicotine, knockin mice were generated in which the threonine codon at position 529 was mutated to an alanine codon. Compared to Chrna4 T529 littermate controls, the Chrna4 A529 knockin mice exhibited greater sensitivity to the hypothermic effects of nicotine, reduced oral nicotine consumption and did not develop conditioned place preference to nicotine. The Chrna4 A529 knockin mice also differed from T529 littermates for two parameters of acetylcholine-stimulated 86Rb+ efflux in midbrain: maximal efflux and the percentage of α4β2* receptors with high sensitivity to activation by agonists. Results indicate that the polymorphism affects the function of midbrain α4β2* nAChRs and contributes to individual differences in several behavioral and physiological responses to nicotine thought to be modulated by midbrain α4β2* nAChRs.

Approximately 80% of smokers initiate tobacco use during adolescence, suggesting that nicotine initiation and nicotine dependence have a substantial age component. There also is a substantial genetic influence on smoking behaviors such as age of initiation and the development of nicotine dependence. The goal of this study was to examine both genetic background and age dependent effects on oral nicotine self-administration and anxiety-like behaviors in mice. Two inbred mouse strains (C3H/Ibg and C57BL/6J) were assessed for oral nicotine preference during early adolescence (postnatal day 24–35), middle adolescence (postnatal day 36–47), late adolescence (postnatal day 48–59), adulthood (postnatal day 60+) and 2 months following their initial exposure to nicotine. Mice also were assessed for innate anxiety using an elevated zero maze to determine if age and/or genetic background influenced anxiety-like behaviors. Results indicated that initial nicotine preference and nicotine preference two months after an initial exposure are both strain and age dependent. Age also had an effect on some baseline anxiety measures but strain differences for most zero maze measures were present throughout all age groups. In general, early adolescent C3H mice exhibited greater nicotine preference while C57 mice displayed greater preference during middle adolescence and upon a second exposure to nicotine. In contrast, C57 mice exhibited reduced anxiety across all ages tested. These studies indicate that genetic background should be considered when evaluating age-dependent effects of drugs of abuse and baseline anxiety-like behaviors.

Ultrasound assisted catheter-directed thrombolysis (UACT) is a relatively novel approach to treating acute pulmonary embolism (PE). It is an alternative to systemic thrombolysis with good success rates and low reported in-hospital mortality, and low rates of procedure-related major and minor bleeding.Since UACT received FDA approval for the treatment of PE in 2014, there is paucity of data regarding the optimal timing of initiation of the procedure after the initial diagnosis is made. We reviewed the available literature regarding UACT for acute PE and found six studies that included time to procedure. Based on our review, patients may benefit from early (<24-48 h after presentation) rather than delayed (>48 h) initiation.Early initiation of therapy has shown to improve pulmonary arterial pressures, right ventricular (RV) to left ventricular (LV) ratios, with low rates of bleeding and low post procedural and in hospital mortality.However, further studies are required to confirm these findings and establish the appropriate timeline for initiation of UACT.

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