ß-Adrenergic control of sarcolemmal CaV1.2 abundance by small GTPase Rab proteins.

The number and activity of Cav1.2 channels in the cardiomyocyte sarcolemma tunes the magnitude of Ca2+-induced Ca2+ release and myocardial contraction. ß-Adrenergic receptor (ßAR) activation stimulates sarcolemmal insertion of CaV1.2. This supplements the preexisting sarcolemmal CaV1.2 population, forming large "superclusters" wherein neighboring channels undergo enhanced cooperative-gating behavior, amplifying Ca2+ influx and myocardial contractility. Here, we determine this stimulated insertion is fueled by an internal reserve of early and recycling endosome-localized, presynthesized CaV1.2 channels. ßAR-activation decreased CaV1.2/endosome colocalization in ventricular myocytes, as it triggered "emptying" of endosomal CaV1.2 cargo into the t-tubule sarcolemma. We examined the rapid dynamics of this stimulated insertion process with live-myocyte imaging of channel trafficking, and discovered that CaV1.2 are often inserted into the sarcolemma as preformed, multichannel clusters. Similarly, entire clusters were removed from the sarcolemma during endocytosis, while in other cases, a more incremental process suggested removal of individual channels. The amplitude of the stimulated insertion response was doubled by coexpression of constitutively active Rab4a, halved by coexpression of dominant-negative Rab11a, and abolished by coexpression of dominant-negative mutant Rab4a. In ventricular myocytes, ßAR-stimulated recycling of CaV1.2 was diminished by both nocodazole and latrunculin-A, suggesting an essential role of the cytoskeleton in this process. Functionally, cytoskeletal disruptors prevented ßAR-activated Ca2+ current augmentation. Moreover, ßAR-regulation of CaV1.2 was abolished when recycling was halted by coapplication of nocodazole and latrunculin-A. These findings reveal that ßAR-stimulation triggers an on-demand boost in sarcolemmal CaV1.2 abundance via targeted Rab4a- and Rab11a-dependent insertion of channels that is essential for ßAR-regulation of cardiac CaV1.2.

A conceptual framework for a neurophysiological basis of art therapy for PTSD.

Post-traumatic stress disorder (PTSD) is a heterogeneous condition that affects many civilians and military service members. Lack of engagement, high dropout rate, and variable response to psychotherapy necessitates more compelling and accessible treatment options that are based on sound neuroscientific evidence-informed decision-making. Art therapy incorporates elements proven to be effective in psychotherapy, such as exposure, making it a potentially valuable treatment option. This conceptual paper aims to inform the neurophysiological rationale for the use of art therapy as a therapeutic approach for individuals with PTSD. A narrative synthesis was conducted using literature review of empirical research on the neurophysiological effects of art therapy, with supporting literature on neuroaesthetics and psychotherapies to identify art therapy factors most pertinent for PTSD. Findings were synthesized through a proposed framework based on the triple network model considering the network-based dysfunctions due to PTSD. Art therapy's active components, such as concretization and metaphor, active art engagement, emotion processing and regulation, perspective taking and reframing, and therapeutic alliance, may improve symptoms of PTSD and prompt adaptive brain functioning. Given the scarcity of rigorous studies on art therapy's effectiveness and mechanisms of alleviating PTSD symptoms, the suggested framework offers a neurophysiological rationale and a future research agenda to investigate the impact of art therapy as a therapeutic approach for individuals with PTSD.

Exploring the evocative qualities of masks' visual imagery and their associations with adversity and trauma.

Introduction: Studies suggest a relationship between the emotional evocativeness of visual imagery and viewer responses, however, there is limited understanding of these associations, especially as they relate to viewers' personal experiences of adversities. Methods: In this exploratory study, we examined the relationship between the visual content of mask images and viewers' responses. In an online survey 699 participants (of n = 1,010 total initial participants) rated 98 masks based on valence, arousal, and personal relevance and completed the Life Events Checklist. The masks included those created by service members (SMs) with traumatic brain injury (TBI), and post-traumatic stress disorder (PTSD), depicting physical, psychological, and moral injuries and matched neutral masks created by creative arts therapists and arts in health scholars. Findings: The findings indicated that responses to mask image content (traumatic versus neutral) were associated with viewers' personal history of adversity and trauma. Specifically, images representing injury/trauma provoked stronger reactions on valence and arousal than neutral images. Moreover, participants with personal histories of trauma had heightened emotional responses to distressing imagery. Discussion: These findings have implications for art therapists as well as for clinical and general populations in that these results highlight the potential impact of distressing imagery particularly for individuals with personal histories of experiencing or witnessing traumatic events.

BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts.

Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac CaV1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca2+ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.

Non-reporting of reportable deaths to the coroner: when in doubt, report.

OBJECTIVE: To better understand the non-reporting of reportable deaths by determining the frequency and nature of reportable deaths referred to the Coroners Court of Victoria (CCOV) by the Registry of Births, Deaths and Marriages (BDM). DESIGN AND SETTING: Review of referrals from BDM to the CCOV between 2003 and 2011 where an external cause of death was recorded on the death certificate, with detailed review for the period 1 July 2010 to 30 June 2011. MAIN OUTCOME MEASURES: Frequency and nature of deaths referred, accuracy of cause of death recorded on death certificate, and degree of change made to cause of death after investigation. RESULTS: Over 9 years, there were 4283 referrals (annual mean, 476). Of 656 deaths referred between 1 July 2010 and 30 June 2011, 320 (48.8%) were found to be reportable. Most causes of death related to injuries; less common were choking, deaths after medical procedures, poisoning and transport-related deaths. Most of the deceased were women (55.9%), were aged ≥ 80 years (80.0%), and died in hospital (68.4%). In 309 cases (96.6%), the coroner changed the cause of death after investigation, with a major change in 146 (45.6%), minor change in 160 (50.0%), and deletion of comorbidities in three (0.9%). Twenty-one cases (6.6%) were investigated further, with one proceeding to an inquest. CONCLUSIONS: Deaths referred by BDM represent a proportion of the unquantified pool of non-reported deaths. Non-reporting of potentially reportable deaths and inaccurate completion of death certificates have significant implications for the health system and community. Further education of medical practitioners about reportable deaths and death certificates is required. Doctors should report any death about which they have doubt.

High-Fructose, High-Fat Diet Alters Muscle Composition and Fuel Utilization in a Juvenile Iberian Pig Model of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a serious metabolic condition affecting millions of people worldwide. A "Western-style diet" has been shown to induce pediatric NAFLD with the potential disruption of skeletal muscle composition and metabolism. To determine the in vivo effect of a "Western-style diet" on pediatric skeletal muscle fiber type and fuel utilization, 28 juvenile Iberian pigs were fed either a control diet (CON) or a high-fructose, high-fat diet (HFF), with or without probiotic supplementation, for 10 weeks. The HFF diets increased the total triacylglycerol content of muscle tissue but decreased intramyocellular lipid (IMCL) content and the number of type I (slow oxidative) muscle fibers. HFF diets induced autophagy as assessed by LC3I and LC3II, and inflammation, as assessed by IL-1α. No differences in body composition were observed, and there was no change in insulin sensitivity, but HFF diets increased several plasma acylcarnitines and decreased expression of lipid oxidation regulators PGC1α and CPT1, suggesting disruption of skeletal muscle metabolism. Our results show that an HFF diet fed to juvenile Iberian pigs produces a less oxidative skeletal muscle phenotype, similar to a detraining effect, and reduces the capacity to use lipid as fuel, even in the absence of insulin resistance and obesity.