Effects of the T-type calcium channel CaV3.2 R1584P mutation on absence seizure susceptibility in GAERS and NEC congenic rats models.

RATIONALE: Low-voltage-activated or T-type Ca2+ channels play a key role in the generation of seizures in absence epilepsy. We have described a homozygous, gain of function substitution mutation (R1584P) in the CaV3.2 T-type Ca2+ channel gene (Cacna1h) in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). The non-epileptic control (NEC) rats, derived from the same original Wistar strains as GAERS but selectively in-breed not to express seizures, are null for the R1584P mutation. To study the effects of this mutation in rats who otherwise have a GAERS or NEC genetic background, we bred congenic GAERS-Cacna1hNEC (GAERS null for R1584P mutation) and congenic NEC-Cacna1hGAERS (NEC homozygous for R1584P mutation) and evaluated the seizure and behavioral phenotype of these strains in comparison to the original GAERS and NEC strains. METHODS: To evaluate seizure expression in the congenic strains, EEG electrodes were implanted in NEC, GAERS, GAERS-Cacna1hNEC without the R1584P mutation, and NEC-Cacna1hGAERS with the R1584P mutation rats. In the first study, continuous EEG recordings were acquired from week 4 (when seizures begin to develop in GAERS) to week 14 of age (when GAERS display hundreds of seizures per day). In the second study, the seizure and behavioral phenotype of GAERS and NEC-Cacna1hGAERS strains were evaluated during young age (6 weeks of age) and adulthood (16 weeks of age) of GAERS, NEC, GAERS-Cacna1hNEC and NEC-Cacna1hGAERS. The Open field test (OFT) and sucrose preference test (SPT) were performed to evaluate anxiety-like and depressive-like behavior, respectively. This was followed by EEG recordings at 18 weeks of age to quantify the seizures, and spike-wave discharge (SWD) cycle frequency. At the end of the study, the whole thalamus was collected for T-type calcium channel mRNA expression analysis. RESULTS: GAERS had a significantly shorter latency to first seizures and an increased number of seizures per day compared to GAERS-Cacna1hNEC. On the other hand, the presence of the R1584P mutation in the NEC-Cacna1hGAERS was not enough to generate spontaneous seizures in their seizure-resistant background. 6 and 16-week-old GAERS and GAERS-Cacna1hNEC rats showed anxiety-like behavior in the OFT, in contrast to NEC and NEC-Cacna1hGAERS. Results from the SPT showed that the GAERS developed depressive-like in the SPT compared to GAERS-Cacna1hNEC, NEC, and NEC-Cacna1hGAERS. Analysis of the EEG at 18 weeks of age showed that the GAERS had an increased number of seizures per day, increased total seizure duration and a higher cycle frequency of SWD relative to GAERS-Cacna1hNEC. However, the average seizure duration was not significantly different between strains. Quantitative real-time PCR showed that the T-type Ca2+ channel isoform CaV3.2 channel expression was significantly increased in GAERS compared to NEC, GAERS-Cacna1hNEC and NEC-Cacna1hGAERS. The presence of the R1584P mutation increased the total ratio of CaV3.2 + 25/-25 splice variants in GAERS and NEC-Cacna1hGAERS compared to NEC and GAERS-Cacna1hNEC. DISCUSSION: The data from this study demonstrate that the R1584P mutation in isolation on a seizure-resistant NEC genetic background was insufficient to generate absence seizures, and that a GAERS genetic background can cause seizures even without the mutation. However, the study provides evidence that the R1584P mutation acts as a modulator of seizures development and expression, and depressive-like behavior in the SPT, but not the anxiety phenotype of the GAERS model of absence epilepsy.

Supporting children's mental health in primary schools: a qualitative exploration of educator perspectives.

Schools are often seen as a key setting for the provision of mental health support for children. This study aimed to explore the professional perspectives of primary school educators in Victoria, Australia, regarding how schools can support the mental health of their students. Semi-structured interviews and focus groups were conducted with 17 primary school educators, from four schools. Thematic analysis was used to generate themes from the data. This study indicates that educators report significant concerns about the complexities of their role and their capacity to support children's mental health due to a lack of resources, overwhelming demands, and inadequate training. Educators highlighted the importance of partnership and communication with families and of a school culture that prioritises mental health. This study provides insights into external factors that can undermine effective support of children's mental health within primary schools and indicates a need for a more integrated approach to supporting children's mental health across education and healthcare.

Testing of a synthetic phonics-based targeted reading intervention for students with reading difficulties in Year 1: protocol for an efficacy randomised controlled trial.

INTRODUCTION: Literacy is fundamental for educational achievement, and in the longer term contributes substantially to a range of life skills. Literacy difficulties during the early years of school are associated with long-term impacts on academic success, with differences in academic achievement sustained through children's schooling. Therefore, addressing literacy difficulties during the early years of school is essential in reducing the risk of children progressing onto negative academic, psychosocial and vocational trajectories. This trial will determine whether a phonics-based reading intervention can improve the reading comprehension of students identified as low-progress readers in the second year of primary school. METHODS/DESIGN: We recruited 236 students fromnine schools after screening for reading difficulties in the second year of primary school (Year 1). Schools in Sydney and Central Coast of New South Wales will be invited to participate via an opt-out consent process. All children identified as being in the bottom 25th percentile using the Wheldall Assessment of Reading Lists will be eligible for the trial. These children will be randomised into either 'usual teaching' or 'intervention' groups. Trained school support teachers will deliver the MiniLit intervention. Intervention: In groups of four, children will complete a daily 1-hour lesson with their MiniLit teacher over 20 school weeks. Follow-up: Immediately after intervention completion and 6 months later using child face-to-face assessments. Primary outcome: Reading comprehension at 6 months after intervention completion. The study will have an embedded process and cost-effectiveness evaluation. DISCUSSION: The Building Better Readers trial will be the first efficacy randomised controlled trial comparing usual teaching with a phonics-based reading intervention for children with reading difficulties in Year 1 of primary school in Australia. The randomised design will limit the effect of bias on outcomes seen in other studies. TRIAL REGISTRATION NUMBER: ACTRN12617000179336.

Proarrhythmia of circumferential left atrial lesions for management of atrial fibrillation.

BACKGROUND: After circumferential ablation for atrial fibrillation, new onset left atrial flutter (LA Flr) may occur. This study assessed the relationship between induced and clinical episodes of LA Flr, the rate of spontaneous resolution of LA Flr, and the proarrhythmic effect of circumferential ablation. METHODS AND RESULTS: A total 112 patients underwent circumferential LA ablation for atrial fibrillation. Immediately after completion of the ablation, LA Flr was induced in 43 of 112 (38%) patients, but was not targeted for ablation. During follow-up (14 +/- 4 months), new onset LA Flr occurred in 28 of 112 (25%) patients; however, the presence of inducible LA Flr did not identify those patients with clinical LA Flr (P = 0.6). In comparison to episodes of atrial fibrillation occurring before circumferential ablation, LA Flr was associated with a faster ventricular rate (124 +/- 19 beats/min vs 91 +/- 16 beats/min, P < 0.001), and was more likely to be persistent requiring cardioversion (86% vs 32%, P = 0.01). By >or=4 months postcircumferential ablation, clinical LA Flr resolved in 18 of 28 patients (64%). A second ablation procedure for LA Flr was performed in 9 of 10 patients. Of the 17 morphologies, 16 (94%) LA Flr circuits were successfully ablated. CONCLUSIONS: (1) LA Flrs that are induced immediately after circumferential ablation for atrial fibrillation do not identify those patients who require a second ablation procedure for clinical LA Flr; (2) Since the majority of clinical LA Flrs spontaneously resolve, ablation of LA Flr should be postponed several months; and (3) new onset LA Flr after ablation for atrial fibrillation is likely a manifestation of the proarrhythmic effect of ablation lines in the LA.