Expression of mRNA encoding G protein-coupled receptors involved in congestive heart failure

Congestive heart failure (CHF) induces changes in the neurohumoral system and gene expression in viable myocardium. Several of these genes encode G protein-coupled receptors (GPCRs) involved in mechanisms which compensate for impaired myocardial function. We used real-time quantitative RT-PCR (Q-RT-PCR) to investigate the expression of mRNA encoding 15 different GPCRs possibly involved in CHF, and the effect of normalisation to GAPDH mRNA (GAPDH) or 18S rRNA (18S). CHF was induced in rats by coronary artery ligation, with sham-operated controls (Sham). After 6 weeks, mRNA expression in viable left ventricular myocardium was determined using both 18S and GAPDH as the normalisation standard. An apparent 30% reduction in GAPDH mRNA levels vs. 18S in CHF compared to Sham, although not significant in itself, influenced the interpretation of regulation of other genes.Thus, levels of mRNA encoding receptors for angiotensin II (AT₁), endothelin (ET_A, ET_B) and the muscarinic acetylcholine (mACh) receptor M₁ increased significantly in CHF only when normalised to GAPDH. Levels of mRNA encoding the mACh receptors M₃ and M₄ and the serotonin receptors 5-HT_2A and 5-HT₄ increased, whereas α_1D-adrenoceptor mRNA decreased in CHF irrespective of the normalisation standard. No significant change was detected for M2 and M5 mACh receptors or α_1A-, α_1B-, β₁- or β₂-adrenoceptors. Q-RT-PCR is a sensitive and powerful method to monitor changes in GPCR mRNA expression in CHF. However, the normalisation standard used is important for the interpretation of mRNA regulation. This article is accompanied by the Invited Editorial "Pitfalls in the normalization of real-time polymerase chain reaction data" by M. C. Hendriks-Balk et al. which can be found under     

Effects of treatment with a 5-HT4 receptor antagonist in heart failure

BACKGROUND AND PURPOSE: Positive inotropic responses (PIR) to 5-hydroxytryptamine (5-HT) are induced in the left ventricle (LV) in rats with congestive heart failure (CHF); this is associated with upregulation of the G(s)-coupled 5-HT(4) receptor. We investigated whether chronic 5-HT(4) receptor blockade improved cardiac function in CHF rats. EXPERIMENTAL APPROACH: Rats were given either the 5-HT(4) antagonist SB207266 (0.5 mg kg(-1) 24h(-1); MI(int)) or placebo (MI(pl)) through mini-osmotic pumps for 6 weeks subsequent to induction of post-infarction CHF. In vivo cardiac function and ex vivo responses to isoprenaline or 5-HT were evaluated using echocardiography and isolated LV papillary muscles, respectively. mRNA levels were investigated using real-time quantitative RT-PCR. KEY RESULTS: LV diastolic function improved, with 4.6% lower LV diastolic diameter and 24.2% lower mitral flow deceleration in MI(int) compared to MI(pl). SB207266 reduced LV systolic diameter by 6.1%, heart weight by 10.2% and lung weight by 13.1%. The changes in posterior wall thickening and shortening velocity, cardiac output, LV systolic pressure and (dP/dt)(max), parameters of LV systolic function, did not reach statistical significance. The PIR to isoprenaline (10 microM) increased by 36% and the response to 5-HT (10 microM) decreased by 57% in MI(int) compared to MI(pl). mRNA levels for ANP, 5-HT(4(b)) and 5-HT(2A) receptors, MHCbeta, and the MHCbeta/MHCalpha -ratio were not significantly changed in MI(int) compared to MI(pl). CONCLUSIONS AND IMPLICATIONS: Treatment with SB207266 to some extent improved in vivo cardiac function and ex vivo myocardial function, suggesting a possible beneficial effect of treatment with a 5-HT(4) receptor antagonist in CHF.     

Medication incidents and medication errors in Danish healthcare: A descriptive study based on medication incident reports from the Danish Patient Safety Database, 2014–2018

In Denmark, reporting of safety incidents to the nationwide Danish Patient Safety Database (DPSD) is mandatory. Medication incident reports constitute the largest category of safety reports. We aimed to provide numbers and characteristics of medication incidents and MEs reported to DPSD focusing on medication, their severity and the trends therein. This is a cross-sectional study of medication incident reports for individuals ≥18, submitted to DPSD in 2014–2018. We performed analyses on the (1) medication incident and (2) ME levels. Out of 479 814 incident reports, 61.18% (n = 293 536) were related to individuals ≥70 and 44.6% (n = 213 974) to nursing homes. Most of the events were harmless (70.87%, n = 340 047) and 0.8% (n = 3859) had caused severe harm or death. ME-analysis (n = 444 555) revealed that paracetamol and furosemide were the most frequently reported drugs. The most common drugs for severe and fatal MEs were warfarin, methotrexate, potassium chloride, paracetamol and morphine. When the reporting ratio for all MEs and harmful MEs was considered, other drugs than the most frequently reported ones were found to be associated with harm. We found a large proportion of harmless medication incident reports and reports from community healthcare services and identified high-risk medicines associated with harm.     

Encouraging greater empowerment for adolescents in consent procedures in social science research and policy projects

The United Nations Convention on the Rights of the Child emphasizes the importance of allowing children and adolescents to influence decisions that are important to them following their age and maturity. This paper explores the principles, practices, and implications around using parental versus child/adolescent consent when participating in social science research and policy development. Experiences from two studies are presented: The Confronting Obesity: Co-creating policy with youth (CO-CREATE) and the Health Behaviour in School-aged Children (HBSC) study, a World Health Organization (WHO) Collaborative Cross-National study. Although parental consent may be an important gatekeeper for protecting children and adolescents from potentially harmful research participation, it may also be considered an obstacle to the empowerment of children and adolescents in case they want to share their views and experiences directly. This paper argues that evaluation of possible harm should be left to ethics committees and that, if no harm related to the research participation processes is identified and the project has a clear perspective on collaborating with the target group, adolescents from the age of 12 years should be granted the legal capacity to give consent to participate in the research project. Collaboration with adolescents in the development of the research project is encouraged.