Uncommon presentations of type A quadricuspid aortic valve in the Septuagenarian.

BACKGROUND: Quadricuspid aortic valve (QAV) is a rare congenital anomaly characterized by the presence of four cusps instead of the usual three. It is estimated to occur in less than 0.05% of the population, with Type A (four equal-sized leaflets) accounting for roughly 30% of QAV subtypes. Based on limited clinical series, the usual presentation is progressive aortic valve regurgitation (AR) with symptoms occurring in the fourth to sixth decade of life. Severe aortic valve stenosis (AS) and acute AR are very uncommon. CASE PRESENTATION: We describe two cases of Type A QAV in patients who remained asymptomatic until their seventies with very uncommon presentations: one with severe AS and one with acute, severe AR and flail leaflet. In Case A, a 72-year-old patient with history of moderate AS presents to clinic with progressive exertional dyspnea. During work-up for transcatheter vs. surgical replacement pre-operative computed tomography angiogram (CTA) reveals a quadricuspid aortic valve with severe AS, and the patient undergoes surgical aortic valve replacement. Pre-discharge transthoracic echocardiography (TTE) shows good prosthetic valve function with no gradient or regurgitation. In Case B, a 76-year-old patient is intubated upon arrival to the hospital for acute desaturation, found to have wide open AR on catheterization, and transferred for emergent intervention. Intraoperative TEE reveals QAV with flail leaflet and severe AR. Repair is considered but deferred ultimately due to emergent nature. Post-operative TTE demonstrates good prosthetic valve function with no regurgitation and normal biventricular function. CONCLUSIONS: QAV can present as progressive severe AS and acute AR, with symptoms first occurring in the seventh decade of life. The optimal treatment for QAV remains uncertain. Although aortic valve repair or transcatheter option may be feasible in some patients, aortic valve replacement remains a tenable option.

Emotion regulation and reactivity are associated with cortical thickness in early to mid-childhood.

This study explored the neural correlates of emotion regulation and emotional reactivity in early to mid-childhood. A sample of 96 children (70% White, mid-to-high socioeconomic status) aged 3-8 years provided structural neuroimaging data and caregivers reported on emotion regulation and emotional reactivity. The amygdala, insula, inferior frontal gyrus, anterior cingulate cortex, and medial orbitofrontal cortex were explored as a priori regions of interest (ROIs). ROI analyses revealed that emotion regulation was positively associated with cortical thickness in the insula, whereas emotional reactivity was negatively associated with cortical thickness in the inferior frontal gyrus. Exploratory whole-brain analyses suggested positive associations between emotion regulation and both left superior temporal thickness and right inferior temporal thickness, as well as negative associations between emotional reactivity and left superior temporal thickness. There were no significant associations between emotional regulation or reactivity and amygdala volume or cortical surface area. These findings support the notion that surface area and cortical thickness are distinct measures of brain maturation. In sum, these findings suggest that children may rely on a wider set of neural regions for emotion regulation and reactivity than adults, which is consistent with theories of interactive specialization across the life span.

Influence of naps on sedentary time and physical activity in early childhood.

The objective was to determine if, in preschool-aged children, (1) nap habituality is associated with sedentary time and physical activity (movement behaviors), (2) nap physiology is associated with movement behaviors, and (3) if missing a nap, compared to taking a nap, affects movement behaviors on the same day and subsequent day. A within-subjects (44 children; 4.2 ± 0.6 years; 55.6% female), at-home study examined two experimental conditions (one afternoon each of nap- and wake-promotion with order counterbalanced) one week apart. Movement behaviors were derived from wrist-worn actigraphy (12.1 ± 3.1 days). Average movement behaviors were calculated from the overall study period with experimental days excluded. Movement behaviors were also extracted for the same day and the subsequent day of the two experimental conditions. Polysomnography was recorded during the nap-promoted condition. Children were classified as non-, intermediate-, or habitual-nappers. Although average movement behaviors were different between nap habituality groups, differences were not significant. There were no associations between movement behaviors and nap sleep stages, and no effects for nap condition or condition by nap habituality on same or next day movement behaviors. Findings do not suggest that naps and movement behaviors are related in children. Although a single missed nap was not detrimental to same or next day movement behaviors, future studies should explore effects of multiple days of subsequent nap restriction to examine potential cumulative effects.

Patient values and preferences for antithrombotic therapy in atrial fibrillation. A Narrative Systematic Review.

Guidelines recommend that patients' values and preferences should be considered when selecting stroke prevention therapy for atrial fibrillation (SPAF). However, doing so is difficult, and tools to assist clinicians are sparse. We performed a narrative systematic review to provide clinicians with insights into the values and preferences of AF patients for SPAF antithrombotic therapy. Narrative systematic review of published literature from database inception. RESEARCH QUESTIONS: 1) What are patients' AF and SPAF therapy values and preferences? 2) How are SPAF therapy values and preferences affected by patient factors? 3) How does conveying risk information affect SPAF therapy preferences? and 4) What is known about patient values and preferences regarding novel oral anticoagulants (NOACs) for SPAF? Twenty-five studies were included. Overall study quality was moderate. Severe stroke was associated with the greatest disutility among AF outcomes and most patients value the stroke prevention efficacy of therapy more than other attributes. Utilities, values, and preferences about other outcomes and attributes of therapy are heterogeneous and unpredictable. Patients' therapy preferences usually align with their values when individualised risk information is presented, although divergence from this is common. Patients value the attributes of NOACs but frequently do not prefer NOACs over warfarin when all therapy-related attributes are considered. In conclusion, patients' values and preferences for SPAF antithrombotic therapy are heterogeneous and there is no substitute for directly clarifying patients' individual values and preferences. Research using choice modelling and tools to help clinicians and patients clarify their SPAF therapy values and preferences are needed.

Potential therapeutic approaches for Angelman syndrome.

INTRODUCTION: Angelman syndrome (AS) is a neurodevelopmental disorder caused by deficiency of maternally inherited UBE3A, an ubiquitin E3 ligase. Despite recent progress in understanding the mechanism underlying UBE3A imprinting, there is no effective treatment. Further investigation of the roles played by UBE3A in the central nervous system (CNS) is needed for developing effective therapies. AREA COVERED: This review covers the literature related to genetic classifications of AS, recent discoveries regarding the regulation of UBE3A imprinting, alterations in cell signaling in various brain regions and potential therapeutic approaches. Since a large proportion of AS patients exhibit comorbid autism spectrum disorder (ASD), potential common molecular bases are discussed. EXPERT OPINION: Advances in understanding UBE3A imprinting provide a unique opportunity to induce paternal UBE3A expression, thus targeting the syndrome at its 'root.' However, such efforts have yielded less-than-expected rescue effects in AS mouse models, raising the concern that activation of paternal UBE3A after a critical period cannot correct all the CNS defects that developed in a UBE3A-deficient environment. On the other hand, targeting abnormal downstream cell signaling pathways has provided promising rescue effects in preclinical research. Thus, combined reinstatement of paternal UBE3A expression with targeting abnormal signaling pathways should provide better therapeutic effects.

UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis.

Gated solely by activity-induced changes in intracellular calcium, small-conductance potassium channels (SKs) are critical for a variety of functions in the CNS, from learning and memory to rhythmic activity and sleep. While there is a wealth of information on SK2 gating, kinetics, and Ca(2+) sensitivity, little is known regarding the regulation of SK2 subcellular localization. We report here that synaptic SK2 levels are regulated by the E3 ubiquitin ligase UBE3A, whose deficiency results in Angelman syndrome and overexpression in increased risk of autistic spectrum disorder. UBE3A directly ubiquitinates SK2 in the C-terminal domain, which facilitates endocytosis. In UBE3A-deficient mice, increased postsynaptic SK2 levels result in decreased NMDA receptor activation, thereby impairing hippocampal long-term synaptic plasticity. Impairments in both synaptic plasticity and fear conditioning memory in UBE3A-deficient mice are significantly ameliorated by blocking SK2. These results elucidate a mechanism by which UBE3A directly influences cognitive function.

Allopregnanolone treatment delays cholesterol accumulation and reduces autophagic/lysosomal dysfunction and inflammation in Npc1-/- mouse brain.

Niemann-Pick Type C (NPC) disease is a devastating developmental disorder with progressive and fatal neurodegeneration. Previous work has shown that a single injection of the neurosteroid allopregnanolone at postnatal day 7 significantly prolonged lifespan of Npc1-/- mice. However, the cellular/molecular basis for this beneficial effect remains undefined. Here, we further characterized the effect of allopregnanolone treatment on cholesterol accumulation, a pathological hallmark of NPC, as well as on autophagic/lysosomal dysfunction, myelination and inflammation in Npc1-/- mouse brains. At 1 month postnatal, accumulation of filipin-labeled unesterified cholesterol was clearly evident not only in neurons but also in microglia in untreated mutant mice, but was mostly absent in allopregnanolone-treated animals. Brain levels of the lysosomal enzymes cathepsins B and D were significantly higher in Npc1-/- than in wild-type mice. Levels of LC3-II, an autophagy marker, were also increased in mutant mouse brain as compared to wild-type mouse brain. Both changes were significantly reduced by allopregnanolone treatment. Injection of the neurosteroid also significantly reduced astrocyte proliferation and microglial activation. Furthermore, allopregnanolone treatment significantly enhanced myelination in mutant mice. Taken together, our results clearly show that allopregnanolone treatment not only reduces cholesterol accumulation and improves autophagic/lysosomal function but also enhances myelination and reduces inflammation. These results provide further support for the potential usefulness of allopregnanolone for treating NPC disease.