Barronoutzen5305

Individual variability in the response to pharmacological therapies is a major problem in the treatment of psychiatric disorders. Comparative studies of phenotypes expressed by mice of the C57BL/6J (C57) and DBA/2J (DBA) inbred strains can help identify neurobiological determinants of this variability at preclinical levels. We have recently demonstrated that whereas young adult mice of both strains develop sign-tracking in a Pavlovian Conditioned Approach (PCA), a trait associated with dysfunctional behavior in rat models, in full adult C57 mice acquisition of this phenotype is inhibited by pre-frontal cortical (PFC) serotonin (5HT) transmission. These findings suggest a different role of 5HT transmission on sign-tracking development in mice of the two genotypes. In the present experiments, we tested the effects of the 5-HT synthesis booster 5-hydroxytryptophan (5-HTP) and of the selective 5HT reuptake inhibitor (SSRI) fluoxetine on the development and expression of sign-tracking in young adult mice from both inbred strains. In mice of the C57 strain, administration of 5-HTP before each training session blocked the training-induced shift to positive PCA scores which indicates the development of sign-tracking, whereas the same treatment was ineffective in mice of DBA strain. On the other hand, a single administration of fluoxetine was ineffective in unhandled saline- and 5-HTP-treated C57 mice, whereas it enhanced the expression of positive PCA scores by mice of DBA strain treated with 5-HTP during training. These findings confirm the strain-specific inhibitory role of PFC 5-HT transmission on sign-tracking development by mice of the C57 strain and support the hypothesis that different genotype-specific neurobiological substrates of dysfunctional phenotypes contribute to variable effects of pharmacotherapies.Cannabis has been used for centuries for its medicinal properties. Given the dangerous and unpleasant side effects of existing analgesics, the chemical constituents of Cannabis have garnered significant interest for their antinociceptive, anti-inflammatory and neuroprotective effects. To date, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) remain the two most widely studied constituents of Cannabis in animals. These studies have led to formulations of THC and CBD for human use; however, chronic pain patients also use different strains of Cannabis (sativa, indica and ruderalis) to alleviate their pain. These strains contain major cannabinoids, such as THC and CBD, but they also contain a wide variety of cannabinoid and noncannabinoid constituents. Although the analgesic effects of Cannabis are attributed to major cannabinoids, evidence indicates other constituents such as minor cannabinoids, terpenes and flavonoids also produce antinociception against animal models of acute, inflammatory, neuropathic, muscle and orofacial pain. In some cases, these constituents produce antinociception that is equivalent or greater compared to that produced by traditional analgesics. Thus, a better understanding of the extent to which these constituents produce antinociception alone in animals is necessary. IMT1B The purposes of this review are to (1) introduce the different minor cannabinoids, terpenes, and flavonoids found in Cannabis and (2) discuss evidence of their antinociceptive properties in animals.

Hypertension remains a leading risk factor for heart failure with preserved ejection fraction (HFpEF), and elevated blood pressure (BP) portends an adverse prognosis in patients with established HFpEF. We summarize current evidence for mechanisms linking hypertension to HFpEF and management of hypertension in HFpEF.

Data suggest a complex, multifactorial pathophysiology driving the association between hypertension and HFpEF, including left ventricular hypertrophy, diastolic dysfunction, atrial dysfunction, coronary microvascular disease, endothelial dysfunction, myocardial injury and fibrosis. Although intensive BP control may attenuate these processes, this hypothesis has not been tested on clinical outcomes in a dedicated randomized controlled trial (RCT) in HFpEF. Antihypertensive therapies variably improve key surrogate markers in HFpEF, though BP reduction generally does not account for these benefits. Accordingly, BP targets are extrapolated from observational studies and RCTs testing heart failure therapies that affect BP in addition to dedicated RCT data in patients at elevated risk (without heart failure).

Clinicians should recognize the risk of disease progression and poor outcomes associated with uncontrolled hypertension in HFpEF. Intensive BP control, preferably by therapies known to improve outcomes in heart failure, may slow key pathways in disease progression. Future RCTs testing intensified BP control strategies in HFpEF are warranted.

Clinicians should recognize the risk of disease progression and poor outcomes associated with uncontrolled hypertension in HFpEF. Intensive BP control, preferably by therapies known to improve outcomes in heart failure, may slow key pathways in disease progression. Future RCTs testing intensified BP control strategies in HFpEF are warranted.

The development of mRNA vaccines against coronavirus disease 2019 has brought worldwide attention to the transformative potential of RNA-based therapeutics. The latter is essentially biological software that can be rapidly designed and generated, with an extensive catalog of applications. This review aims to highlight the mechanisms of action by which RNA-based drugs can affect specific gene targets and how RNA drugs can be employed to treat cardiovascular disease, with the focus on the therapeutics being evaluated in clinical trials. The recent advances in nanotechnology aiding the translation of such therapies into the clinic are also discussed.

There is a growing body of studies demonstrating utility of RNA for targeting previously 'undruggable' pathways involved in development and progression of cardiovascular disease. Some challenges in RNA delivery have been overcome thanks to nanotechnology. There are several RNA-based drugs to treat hypercholesterolemia and myocardial infarction which are currently in clinical trials.