Chronic pharmacological activation of SERCA with CDN1163 affects spatial cognitive flexibility but not attention and impulsivity in mice.

Intracellular calcium (Ca2+) homeostasis is critical for many neural processes, including learning, memory and synaptic plasticity. The sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) is among the key regulators that preserve Ca2+ homeostasis in neurons. SERCAs comprise a set of ubiquitously expressed Ca2+ pumps that primarily function to sequester cytosolic Ca2+ into endoplasmic reticular stores. As SERCA has been implicated in the neurobiology of several neuropsychiatric and neurodegenerative diseases, pharmacological harnessing of its function is critical in understanding SERCA's role in brain physiology and pathophysiology. In the current study, we employed the Morris water maze and 5-choice serial reaction time task (5-CSRTT) to investigate the effects of chronic pharmacological activation of SERCA, using the small allosteric SERCA activator CDN1163, on spatial learning and memory, and executive functioning in naive C57BL/6J mice. Our data show that chronic pharmacological SERCA activation with CDN1163 (20 mg/kg) selectively impairs spatial cognitive flexibility and reversal learning in the Morris water maze while leaving executive functions such as attention and impulsivity intact. Present findings contribute to the growing field of the role of SERCA function in the brain and behavior and expand current knowledge on the use of the small allosteric activator CDN1163 as an investigational tool to study the role of SERCA in regulating neurobehavioral processes and as a potential therapeutic candidate for debilitating brain disorders.

Insights into the role of intracellular calcium signaling in the neurobiology of neurodevelopmental disorders.

Calcium (Ca2+) comprises a critical ionic second messenger in the central nervous system that is under the control of a wide array of regulatory mechanisms, including organellar Ca2+ stores, membrane channels and pumps, and intracellular Ca2+-binding proteins. Not surprisingly, disturbances in Ca2+ homeostasis have been linked to neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. However, aberrations in Ca2+ homeostasis have also been implicated in neuropsychiatric disorders with a strong neurodevelopmental component including autism spectrum disorder (ASD) attention-deficit hyperactivity disorder (ADHD) and schizophrenia (SCZ). While plasma membrane Ca2+ channels and synaptic Ca2+-binding proteins have been extensively studied, increasing evidence suggests a prominent role for intracellular Ca2+ stores, such as the endoplasmic reticulum (ER), in aberrant neurodevelopment. In the context of the current mini-review, we discuss recent findings implicating critical intracellular Ca2+-handling regulators such as the sarco-ER Ca2+ ATPase 2 (SERCA2), ryanodine receptors (RyRs), inositol triphosphate receptors (IP3Rs), and parvalbumin (PVALB), in the emergence of ASD, SCZ, and ADHD.

Consumer opinions on adverse events associated with medical devices.

INTRODUCTION: Post-market surveillance of medical devices relies on compulsory and voluntary reports. Although direct consumer reporting of medical device-related adverse events (AEs) is available in Australia, the proportion of consumer reports has remained low. Limited qualitative research has previously explored consumer insights on AEs associated with medical devices and in particular, AE reporting. OBJECTIVE: To explore consumer opinions on AEs related to medical devices, and their knowledge of, experiences with, and views on, the reporting of medical device-related AEs. METHODS: Focus groups (n = 4; total of 29 participants) were conducted in metropolitan Sydney, Australia. Focus group discussions of approximately 1.5 h in length centred on consumers' understanding of AEs, opinions on AEs and their previous experiences, views on medical device benefits and harms, and actions taken (or potential actions) in response to AEs. With participant consent, discussions were audio-recorded, transcribed verbatim, and thematically analysed. RESULTS: Participants regarded medical device-related side effects to be unexpected AEs associated with their use. Where there was a clear need for the medical device itself, potential improvement in quality of life took precedence over potential harms. Most participants had not experienced negative issues with their medical device(s). There was poor awareness among participants of an existing direct consumer AE reporting system for medical devices. Despite this, the value of reporting was acknowledged. Severity of the AE was a key motivator for potential AE reporting. CONCLUSIONS: Further efforts are necessary to improve consumer awareness of available AE reporting systems to better support post-market surveillance and safe medical device use.

Consumer opinions on adverse events associated with medicines and vaccines.

INTRODUCTION: Despite the availability of an Australian consumer adverse event (AE) reporting system for over 50 years, reporting rates remain low. A comprehensive understanding of consumer perceptions and experiences regarding AEs is needed to further ascertain factors impacting their engagement in AE reporting. AIM: The aim of this study was to explore consumer opinions about AEs potentially associated with medicines and vaccines, and their experiences and understanding of managing and reporting AEs. METHODS: Six focus groups were conducted across metropolitan Sydney with a total of 48 adult participants. A semi-structured focus group topic guide was developed to explore consumers' understanding, experiences, and actions taken in relation to AEs; and perspectives on managing treatment benefits and harms. Discussions were audio-recorded with participant permission and transcribed verbatim. Transcripts were thematically analyzed. RESULTS: Consumers acknowledged the potential for side effects (SEs), however inaccurately estimated SE risk in response to verbal descriptors such as "common." Consumer appraisal of treatment benefits and harms was influenced by factors such as medical condition(s), previous experiences, and beliefs. Although many had experienced SEs, consumers only reported them if considered severe or troublesome. Minimal awareness of consumer AE reporting systems was evident. Doctors were the primary avenue for reporting; consumers preferred doctors to act as the intermediary in reporting AEs to an independent body. CONCLUSION: Consumers' lack of awareness of AE reporting systems was evident. With the complexities inherent in benefit/harm risk appraisal, information seeking, and AE reporting preferences, better consumer understanding of AEs and the systems available for reporting is needed.