Non-technical summary Alterations in synaptic efficacy are thought to underlie changes in learning and behaviour and are vital to normal neuronal function. Using a variety of different cells and techniques we investigate whether anaesthetics can modify neurotransmitter release as part of their mechanism of action. Our data suggest that inhibition of neurotransmitter release may be a critical mechanism for the actions of anaesthetics like etomidate and propofol. In the future this information may be used to design new generations of clinically useful anaesthetics. AbstractThe mechanism of general anaesthetic action is only partially understood. Facilitation of inhibitory GABA A receptors plays an important role in the action of most anaesthetics, but is thought to be especially relevant in the case of intravenous anaesthetics, like etomidate and propofol. Recent evidence suggests that anaesthetics also inhibit excitatory synaptic transmission via a presynaptic mechanism(s), but it has been difficult to determine whether these agents act on the neurotransmitter release machinery itself. In the present study we sought to determine whether the intravenous anaesthetics propofol and etomidate inhibit the release machinery. For these studies we used an experimental approach that directly regulated [Ca 2+ ] i at neurotransmitter release sites, thereby bypassing anaesthetic effects on channels and receptors in order to allow anaesthetic effects on the neurotransmitter release machinery to be examined in isolation. The data show that clinically relevant concentrations of propofol and etomidate inhibited the neurotransmitter release machinery in neurosecretory cells and in cultured hippocampal neurons. md130A is a mutant form of syntaxin with a truncated C-terminus. Overexpressing md130A in PC12 cells completely eliminated the reduction in neurotransmitter release produced by propofol, without affecting release itself. In contrast, overexpressing md130A in PC12 cells had little or no effect on the response to etomidate. These results suggest that both propofol and etomidate inhibit neurotransmitter release by a direct interaction with SNAREs and/or SNARE-associated proteins but they do so at different sites.

Reduction mammaplasty was significantly associated with improvements in health-related quality of life and breast-related symptoms of adolescent patients, with measureable improvements in physical and psychosocial well-being evident by 6 months postoperatively and still demonstrable after 5-years. These results largely do not vary by BMI category or age. Patients and providers should be aware of the potential positive impact that reduction mammaplasty can provide adolescents with symptomatic macromastia. Historic concerns regarding age and BMI category at the time of surgery should be reconsidered.

General anesthetics produce anesthesia by depressing central nervous system activity. Activation of inhibitory GABA(A) receptors plays a central role in the action of many clinically relevant general anesthetics. Even so, there is growing evidence that anesthetics can act at a presynaptic locus to inhibit neurotransmitter release. Our own data identified the neurotransmitter release machinery as a target for anesthetic action. In the present study, we sought to examine the site of anesthetic action more closely. Exocytosis was stimulated by directly elevating the intracellular Ca(2+) concentration at neurotransmitter release sites, thereby bypassing anesthetic effects on channels and receptors, allowing anesthetic effects on the neurotransmitter release machinery to be examined in isolation. Three different PC12 cell lines, which had the expression of different release machinery proteins stably suppressed by RNA interference, were used in these studies. Interestingly, there was still significant neurotransmitter release when these knockdown PC12 cells were stimulated. We have previously shown that etomidate, isoflurane, and propofol all inhibited the neurotransmitter release machinery in wild-type PC12 cells. In the present study, we show that knocking down synaptotagmin I completely prevented etomidate from inhibiting neurotransmitter release. Synaptotagmin I knockdown also diminished the inhibition produced by propofol and isoflurane, but the magnitude of the effect was not as large. Knockdown of SNAP-25 and SNAP-23 expression also changed the ability of these three anesthetics to inhibit neurotransmitter release. Our results suggest that general anesthetics inhibit the neurotransmitter release machinery by interacting with multiple SNARE and SNARE-associated proteins.

Background: Adolescent reduction mammaplasty remains controversial because of concerns of postoperative breast growth, complications, and the effect on well-being. The authors sought to prospectively quantify early and late complications following reduction mammaplasty in adolescents and young women, and examine the intersection of surgical complications and postoperative health-related quality of life. Methods: From 2008 to 2017, female patients aged 12 to 21 years undergoing reduction mammaplasty were asked to complete the 36-Item Short-Form Health Survey (version 2), the Rosenberg Self-Esteem Scale, the Breast-Related Symptoms Questionnaire, and the Eating-Attitudes Test-26 preoperatively and postoperatively at 6 months and 1, 3, 5, and 7 years. Clinical evaluations using standardized forms assessed baseline and postoperative symptomatology, complications, and surgical outcomes. Results: In the authors’ sample of 512 participants, the most common complications included hypertrophic scarring (20.0 percent) and altered sensation of the nipple (8.4 percent) or breast (7.8 percent). Patient age, body mass index category, and amount of tissue resected did not significantly increase the odds of developing a complication. Significant postoperative improvements on the Rosenberg Self-Esteem Scale, the Breast-Related Symptoms Questionnaire, the Eating-Attitudes Test-26, and in all 36-Item Short-Form Health Survey domains (i.e., physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health) were largely seen irrespective of whether complications occurred. Conclusions: Although complications following reduction mammaplasty were common, the vast majority were minor. Patients had significant postoperative improvements in their physical and psychosocial well-being regardless of whether they experienced a complication. Concerns for potential complication, especially in younger and overweight or obese patients, should not preclude otherwise healthy adolescents and young women from the benefits of reduction mammaplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.