Establishing therapeutic and supportive relationships throughout delivery of a school-based group parenting program via telehealth: Exploring causal pathways.

Background: Access to specialised early intervention mental health services for children, including group counselling for parents/carers, is still a challenge in non-metropolitan areas of Australia. Aim: To gain understanding of the acceptability of a school-based targeted parenting group program delivered via telehealth by exploring the experiences of parents/carers, clinicians and school staff, and asking what works, how, why and in what circumstances. Methods: Caregivers, clinicians and school staff involved in the delivery of a mental health program via telehealth into primary schools in two rural Local Health Districts (LHDs) in southern New South Wales (NSW) were invited to participate in interviews and/or focus group discussions. Thematic analysis of the data was conducted with reference to realist theory. Findings: We conducted semi-structured interviews with 12 caregivers, five semi-structured interviews and two focus group discussions with school staff from six participating schools, and three focus groups with seven clinicians who delivered the intervention. We found that the intervention and micro contexts interacted to influence acceptability by initiating or enhancing cohesion among caregivers, establishing channels of communication between caregivers and teachers, and connection between caregivers and clinicians despite geographic distance. Several adaptations were made to strengthen the therapeutic alliance between caregivers and clinicians. Conclusion: Relationships crucial to the success of delivering psychological group counselling were established. Regional community contexts can facilitate acceptability of parenting group counselling delivered into schools via telehealth. Implementation of the program was flexible enough to allow clinicians to adjust their approach and materials to better suit the telehealth modality.

Swallowing assessment in patients with dysphagia: Validity and reliability of a pocket-sized ultrasound system.

BACKGROUND: The use of ultrasound as an adjunct to clinical swallowing evaluation provides quantitative physiological and morphological data. As a low-risk procedure, ultrasound imaging can be performed outside of a medical setting. This is particularly important for patients living in rural areas with restricted access to a hospital. Technical advances have produced pocket-sized ultrasound technology that is more affordable, and therefore within the fiscal reach of most allied health services. AIMS: To explore the validity and reliability of pocket-sized ultrasound technology in dysphagia assessment. METHODS & PROCEDURES: Data were acquired from 43 patients with dysphagia using the Clarius ultrasound device. Ultrasound and videofluoroscopic measures of hyoid and laryngeal displacement during liquid and puree swallowing were collected concurrently to quantify correlation and agreement between identical measures derived from the two instruments. Reliability of ultrasound was assessed for measures of hyoid and laryngeal displacement, tongue thickness, and size of the submental muscles in eight patients. Reliability was evaluated for the entire process of data acquisition including scanning and online measurement using an iPad in a clinical setting and for offline measurement on a computer screen to explore environmental influences on reliability. OUTCOMES & RESULTS: Results revealed poor correlation between the measures of interest across instruments. Reliability of the entire process of data acquisition in a clinical setting was insufficient while reliability was more promising for offline measurements. CONCLUSIONS & IMPLICATIONS: The clinical use of pocket-sized ultrasound devices, such as the Clarius system, for swallowing evaluation is not indicated at this time. Enhanced validity and reliability of the entire process of data acquisition are needed prior to clinical translation of such technology. WHAT THIS PAPER ADDS: What is already known on the subject The use of ultrasound allows for radiation-free, non-invasive swallowing assessment. Some data suggest that ultrasound is valid and reliable in the evaluation of swallowing using standard-sized equipment. Insufficient validity and reliability have been reported for pocket-sized ultrasound technology in the assessment of healthy swallowing. What this paper adds to existing knowledge This research is the first to provide validity and reliability data of the pocket-sized Clarius technology in the evaluation of swallowing in patients with dysphagia. Insufficient validity and reliability of online data acquisition in a clinical environment were found. Reliability for offline measurement was more promising. What are the potential or actual clinical implications of this work? The clinical use of pocket-sized ultrasound devices, such as the Clarius system, for swallowing assessment is not indicated at this time.

Psychedelics as Reemerging Treatments for Anxiety Disorders: Possibilities and Challenges in a Nascent Field.

Although psychedelics initially showed promise in treating anxiety disorders, psychedelics were criminalized and research halted in the early 1970s. A subsequent resurgence of research into psychiatric benefits of psychedelic-assisted psychotherapy in the last 20 years has led to a potential paradigm shift in the treatment of numerous psychiatric disorders, including anxiety disorders. Despite accumulating evidence and likely U.S. Food and Drug Administration approval in the next 2-3 years, the emerging field of psychedelic medicine faces several challenges. Obstacles include ongoing barriers on the regulatory level, lack of education, stigma among mental health clinicians, cost and scalability, and a dearth of specialized personnel prepared to provide these treatments. Deeper issues of ethical responsibility and inclusivity also exist given the historical discovery and use of psychedelics by indigenous peoples throughout the world as well the ongoing disparities in mental health delivery and access within psychiatry and psychedelic research.

Ultrasound: Reliability of a Pocket-Sized System in the Assessment of Swallowing.

Purpose Ultrasound imaging offers a noninvasive adjunct to clinical swallowing assessment. Published reliability of sophisticated ultrasound systems is promising; however, no data exist for reliability using more affordable, pocket-sized devices. This study explored intrarater, interrater, and test-retest reliability of swallowing measures acquired with pocket-sized ultrasound technology. Method Five participants collected measures of swallowing from 20 healthy individuals using the Clarius ultrasound. Hyoid excursion and thyrohyoid approximation were derived during saliva, liquid, and puree swallowing. The cross-sectional area of the floor of mouth muscles and tongue thickness were obtained at rest. Measures were collected at two occasions minimum 11 days apart. Reliability was assessed for the entire process of data acquisition including scanning and online measurement, and for offline measurement of saved images. Results For most measures, reliability was poor (ICC [intraclass correlation coefficient] < .50) to moderate (ICC = .50-.75) for the entire process of data acquisition and poor to good (ICC > .75) when measuring saved images. Conclusion Further work is needed to elucidate whether our study findings apply to the Clarius system only or the data suggest a general limitation of pocket-sized ultrasound technology.

Ultrasound: Validity of a Pocket-Sized System in the Assessment of Swallowing.

Adequate hyoid and laryngeal displacement facilitate safe and efficient swallowing. Although videofluoroscopy is commonly used for assessment of this biomechanical event, ultrasound provides benefits as a radiation-free modality for this purpose. This study investigated validity of a pocket-sized ultrasound system (Clarius™) in the assessment of hyoid and laryngeal excursion. Hyoid excursion and thyrohyoid approximation were concurrently assessed in 20 healthy adults using ultrasound and videofluoroscopy during saliva, liquid, and puree swallowing. Correlation analyses were performed to evaluate validity. There was a strong and moderate positive association between ultrasound and videofluoroscopic measurements of hyoid excursion during dry and liquid swallowing, respectively. No evidence for a significant association was found for ultrasound and videofluoroscopic measurements of hyoid excursion for puree swallowing and of thyrohyoid approximation for any bolus type. Further work towards improved validity is necessary prior to clinical transfer of the pocket-sized Clarius™ system in clinical swallowing assessment.

What do we know about the impact of the Covid-19 pandemic on hospices? A collaborative multi-stakeholder knowledge synthesis.

Background: Prior to undertaking a study looking at the effects of the COVID-19 pandemic upon lived experiences of hospice services in the West Midlands, we sought to identify the range of issues that hospice service users and providers faced between March 2020 and July 2021, and to provide a report that can be accessed and understood by all interested stakeholders. Methods: We undertook a collaborative multi-stakeholder approach for scoping the range of potential issues and synthesising knowledge. This involved a review of available literature; a focus group with hospice stakeholders; and a collaborative knowledge exchange panel. Results: The literature on the effects of the COVID-19 pandemic on hospices remains limited, but it is developing a picture of a service that has had to rapidly adapt the way it provides care and support to its service users, during a period when it faced many fundamental challenges to established ways of providing these services. Results: The impacts of many of the changes on hospices have not been fully assessed. It is also not known what the effects upon the quality of care and support are for those with life-limiting conditions and those that care for them. We found that the pandemic has presented a new normative and service context in which quality of care and life itself was valued that is, as yet, poorly understood.

Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator.

Zuranolone (SAGE-217) is a novel, synthetic, clinical stage neuroactive steroid GABAA receptor positive allosteric modulator designed with the pharmacokinetic properties to support oral daily dosing. In vitro, zuranolone enhanced GABAA receptor current at nine unique human recombinant receptor subtypes, including representative receptors for both synaptic (γ subunit-containing) and extrasynaptic (δ subunit-containing) configurations. At a representative synaptic subunit configuration, α1ß2γ2, zuranolone potentiated GABA currents synergistically with the benzodiazepine diazepam, consistent with the non-competitive activity and distinct binding sites of the two classes of compounds at synaptic receptors. In a brain slice preparation, zuranolone produced a sustained increase in GABA currents consistent with metabotropic trafficking of GABAA receptors to the cell surface. In vivo, zuranolone exhibited potent activity, indicating its ability to modulate GABAA receptors in the central nervous system after oral dosing by protecting against chemo-convulsant seizures in a mouse model and enhancing electroencephalogram ß-frequency power in rats. Together, these data establish zuranolone as a potent and efficacious neuroactive steroid GABAA receptor positive allosteric modulator with drug-like properties and CNS exposure in preclinical models. Recent clinical data support the therapeutic promise of neuroactive steroid GABAA receptor positive modulators for treating mood disorders; brexanolone is the first therapeutic approved specifically for the treatment of postpartum depression. Zuranolone is currently under clinical investigation for the treatment of major depressive episodes in major depressive disorder, postpartum depression, and bipolar depression.

On the same page: Co-designing the logic model of a telehealth service for children in rural and remote Australia.

The value of programme logic models as a tool for planning, evaluation, and communication is well recognised. However, the value of its development process is less discussed. In this paper, we describe how we used a combination of literature review and organisational stakeholder consultations to develop a logic model for a telehealth programme for children in rural and remote Australia. Our aim was to use this process to further embed the programme within its implementing organisation, and by so doing to promote its sustainability and scale-up; a major challenge of telehealth programmes, especially those involving reorganisation of processes. Our efforts to describe the components of this complex intervention on the one-page logic model allowed for debates and discussions within the implementing organisation which then facilitated an improved cross-organisational understanding of the telehealth programme; a real time face-to-face (video-link) service which requires the reorganisation of existing service delivery platforms. The process helped to embed the telehealth programme within existing services. We conclude that stakeholder engagement in developing logic models can transform them from being only a tool that provides the picture of why and how a programme works, to one that plays a role in embedding programmes within implementing organisations.

A Novel, Synthetic, Neuroactive Steroid Is Effective at Decreasing Depression-Like Behaviors and Improving Maternal Care in Preclinical Models of Postpartum Depression.

Preclinical testing of treatments for postpartum depression (PPD) has been limited due to the lack of available animal models of such a complex disorder. To address this limitation, our laboratory has generated unique preclinical mouse models that exhibit abnormal postpartum behaviors. Mice with a loss or reduction in the expression of the GABAA receptor (GABAAR) δ subunit (Gabrd -/- or Gabrd +/-, respectively) and mice that lack the K+/Cl- co-transporter, KCC2, specifically in corticotropin-releasing hormone (CRH) neurons (KCC2/Crh mice) exhibit depression-like behaviors restricted to the postpartum period and deficits in maternal care, which serve as useful tools for testing novel therapeutic compounds. Utilizing these preclinical models, we tested the ability of a novel, synthetic, neuroactive steroid developed by SAGE Therapeutics, SGE-516, to improve abnormal postpartum behaviors. Gabrd -/-, Gabrd +/-, and KCC2/Crh dams treated with SGE-516 (450 mg/kg chow) during late pregnancy exhibit a decrease in depression-like behaviors and improvements in maternal care at 48 h postpartum. Interestingly, acute treatment with SGE-516 also exhibits robust therapeutic effects in these preclinical PPD models. We previously discovered abnormal stress reactivity associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation associated with depression-like behaviors in the preclinical PPD models, evident from an increase in stress-induced corticosterone levels and dephosphorylation and downregulation of KCC2 in the paraventricular nucleus of the hypothalamus (PVN) during the peripartum period. Here we demonstrated that SGE-516 treatment is sufficient to prevent the stress-induced increase in corticosterone and dephosphorylation and downregulation of KCC2 in the PVN. In contrast, and consistent with the distinct pharmacology of SGE-516 compared to benzodiazepines, treatment with clobazam (250 mg/kg chow) did not alter the depression-like phenotype or deficits in maternal care observed in these preclinical models of PPD. These findings are consistent with the positive double-blind, randomized, placebo-controlled trial findings of a similar compound, brexanolone, in the treatment of patients with postpartum depression. Further, these findings validate the use of these preclinical models of PPD for screening novel compounds for the treatment of postpartum depression.

The synthetic neuroactive steroid SGE-516 reduces seizure burden and improves survival in a Dravet syndrome mouse model.

Dravet syndrome is an infant-onset epileptic encephalopathy with multiple seizure types that are often refractory to conventional therapies. Treatment with standard benzodiazepines like clobazam, in combination with valproate and stiripentol, provides only modest seizure control. While benzodiazepines are a first-line therapy for Dravet syndrome, they are limited by their ability to only modulate synaptic receptors. Unlike benzodiazepines, neuroactive steroids potentiate a wider-range of GABAA receptors. The synthetic neuroactive steroid SGE-516 is a potent positive allosteric modulator of both synaptic and extrasynaptic GABAA receptors. Prior work demonstrated anticonvulsant activity of SGE-516 in acute seizure assays in rodents. In this study, we evaluated activity of SGE-516 on epilepsy phenotypes in the Scn1a +/- mouse model that recapitulates many features of Dravet syndrome, including spontaneous seizures, premature death and seizures triggered by hyperthermia. To evaluate SGE-516 in Scn1a +/- mice, we determined the effect of treatment on hyperthermia-induced seizures, spontaneous seizure frequency and survival. SGE-516 treatment protected against hyperthermia-induced seizures, reduced spontaneous seizure frequency and prolonged survival in the Scn1a +/- mice. This provides the first evidence of SGE-516 activity in a mouse model of Dravet syndrome, and supports further investigation of neuroactive steroids as potential anticonvulsant compounds for refractory epilepsies.

(Dis)integrated Care: Barriers to Health Care Utilization for Trans Women Living With HIV.

Transgender (trans) women have been particularly impacted by HIV. To seek insights into the dynamics of health service utilization, interviews were conducted with trans women living with HIV (n = 14) as part of the Trans PULSE community-based research project in Ontario, Canada. Service providers (n = 10) were also interviewed to provide additional details about communication between trans women, social service providers, and clinicians. Results highlight how both problematic interactions with individuals and health systems navigation challenges affect access to services and impede the development of trans-specific HIV supports. Participants described discrimination, identified strategies for navigating a dysfunctional system, and outlined specific ways in which health and social services may be failing trans women living with HIV. Findings support the importance of coordinating HIV services and transition-related care, and providing training for service providers.

Anticonvulsant profile of the neuroactive steroid, SGE-516, in animal models.

Despite the availability of multiple antiepileptic drugs (AED), failure to adequately control seizures is a challenge for approximately one third of epilepsy patients, and new therapies with a differentiated mechanism of action are needed. The neuroactive steroid, SGE-516, is a positive allosteric modulator of both gamma- and delta-containing GABAA receptors. This broad GABAA receptor activity differentiates neuroactive steroids like SGE-516 from benzodiazepines, a class of anticonvulsants which have been shown in vitro to selectively target gamma-subunit containing GABAA receptors. As a neuroactive steroid, SGE-516 has pharmacokinetic properties that are intended to allow for chronic oral dosing. We investigated the anticonvulsant activity of SGE-516 across numerous in vitro and in vivo models of seizure activity. SGE-516 dose-dependently reduced neuronal firing rates and epileptiform activity in vitro. In mice, SGE-516 protected against acute seizures in the PTZ-induced chemo-convulsant seizure model and the 6Hz psychomotor seizure model. In addition, SGE-516 demonstrated anticonvulsant activity in the mouse corneal kindling model. These data suggest that SGE-516 may have potential for development as a novel oral AED for the treatment of refractory seizures.

The synthetic neuroactive steroid SGE-516 reduces status epilepticus and neuronal cell death in a rat model of soman intoxication.

Organophosphorus nerve agents (OPNAs) are irreversible inhibitors of acetylcholinesterase that pose a serious threat to public health because of their use as chemical weapons. Exposure to high doses of OPNAs can dramatically potentiate cholinergic synaptic activity and cause status epilepticus (SE). Current standard of care for OPNA exposure involves treatment with cholinergic antagonists, oxime cholinesterase reactivators, and benzodiazepines. However, data from pre-clinical models suggest that OPNA-induced SE rapidly becomes refractory to benzodiazepines. Neuroactive steroids (NAS), such as allopregnanolone, retain anticonvulsant activity in rodent models of benzodiazepine-resistant SE, perhaps because they modulate a broader variety of GABAA receptor subtypes. SGE-516 is a novel, next generation NAS and a potent and selective GABAA receptor positive allosteric modulator (PAM). The present study first established that SGE-516 reduced electrographic seizures in the rat lithium-pilocarpine model of pharmacoresistant SE. Then the anticonvulsant activity of SGE-516 was investigated in the soman-intoxication model of OPNA-induced SE. SGE-516 (5.6, 7.5, and 10mg/kg, IP) significantly reduced electrographic seizure activity compared to control when administered 20min after SE onset. When 10mg/kg SGE-516 was administered 40min after SE onset, seizure activity was still significantly reduced compared to control. In addition, all cohorts of rats treated with SGE-516 exhibited significantly reduced neuronal cell death as measured by FluoroJade B immunohistochemistry. These data suggest synthetic NASs that positively modulate both synaptic and extrasynaptic GABAA receptors may be candidates for further study in the treatment of OPNA-induced SE.

Factors Impacting Transgender Patients' Discomfort with Their Family Physicians: A Respondent-Driven Sampling Survey.

BACKGROUND: Representing approximately 0.5% of the population, transgender (trans) persons in Canada depend on family physicians for both general and transition-related care. However, physicians receive little to no training on this patient population, and trans patients are often profoundly uncomfortable and may avoid health care. This study examined factors associated with patient discomfort discussing trans health issues with a family physician in Ontario, Canada. METHODS: 433 trans people age 16 and over were surveyed using respondent-driven sampling for the Trans PULSE Project; 356 had a family physician. Weighted logistic regression models were fit to produce prevalence risk ratios (PRRs) via average marginal predictions, for transmasculine (n = 184) and transfeminine (n = 172) trans persons. RESULTS: Among the 83.1% (95% CI = 77.4, 88.9) of trans Ontarians who had a family physician, approximately half reported discomfort discussing trans health issues. 37.2% of transmasculine and 38.1% of transfeminine persons reported at least one trans-specific negative experience. In unadjusted analysis, sociodemographics did not predict discomfort, but those who planned to medically transition sex, but had not begun, were more likely to report discomfort (transmasculine: PRR = 2.62 (95% CI = 1.44, 4.77); transfeminine: PRR = 1.85 (95% CI = 1.08, 3.15)). Adjusted for other factors, greater perceived physician knowledge about trans issues was associated with reduced likelihood of discomfort, and previous trans-specific negative experiences with a family physician with increased discomfort. Transfeminine persons who reported three or more types of negative experiences were 2.26 times as likely, and transmasculine persons 1.61 times as likely, to report discomfort. In adjusted analyses, sociodemographic associations differed by gender, with being previously married or having higher education associated with increased risk of discomfort among transfeminine persons, but decreased risk among transmasculine persons. CONCLUSIONS: Within this transgender population, discomfort in discussing trans health issues with a family physician was common, presenting a barrier to accessing primary care despite having a regular family physician and "universal" health insurance.

A molecular tweezer antagonizes seminal amyloids and HIV infection.

Semen is the main vector for HIV transmission and contains amyloid fibrils that enhance viral infection. Available microbicides that target viral components have proven largely ineffective in preventing sexual virus transmission. In this study, we establish that CLR01, a 'molecular tweezer' specific for lysine and arginine residues, inhibits the formation of infectivity-enhancing seminal amyloids and remodels preformed fibrils. Moreover, CLR01 abrogates semen-mediated enhancement of viral infection by preventing the formation of virion-amyloid complexes and by directly disrupting the membrane integrity of HIV and other enveloped viruses. We establish that CLR01 acts by binding to the target lysine and arginine residues rather than by a non-specific, colloidal mechanism. CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself. These combined anti-amyloid and antiviral activities make CLR01 a promising topical microbicide for blocking infection by HIV and other sexually transmitted viruses.

Epigallocatechin-3-gallate rapidly remodels PAP85-120, SEM1(45-107), and SEM2(49-107) seminal amyloid fibrils.

Semen harbors amyloid fibrils formed by proteolytic fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120) and semenogelins (SEM1 and SEM2) that potently enhance HIV infectivity. Amyloid but not soluble forms of these peptides enhance HIV infection. Thus, agents that remodel these amyloid fibrils could prevent HIV transmission. Here, we confirm that the green tea polyphenol, epigallocatechin-3-gallate (EGCG), slowly remodels fibrils formed by PAP248-286 termed SEVI (semen derived enhancer of viral infection) and also exerts a direct anti-viral effect. We elucidate for the first time that EGCG remodels PAP85-120, SEM1(45-107), and SEM2(49-107) fibrils more rapidly than SEVI fibrils. We establish EGCG as the first small molecule that can remodel all four classes of seminal amyloid. The combined anti-amyloid and anti-viral properties of EGCG could have utility in preventing HIV transmission.

Intervenable factors associated with suicide risk in transgender persons: a respondent driven sampling study in Ontario, Canada.

BACKGROUND: Across Europe, Canada, and the United States, 22-43 % of transgender (trans) people report a history of suicide attempts. We aimed to identify intervenable factors (related to social inclusion, transphobia, or sex/gender transition) associated with reduced risk of past-year suicide ideation or attempt, and to quantify the potential population health impact. METHODS: The Trans PULSE respondent-driven sampling (RDS) survey collected data from trans people age 16+ in Ontario, Canada, including 380 who reported on suicide outcomes. Descriptive statistics and multivariable logistic regression models were weighted using RDS II methods. Counterfactual risk ratios and population attributable risks were estimated using model-standardized risks. RESULTS: Among trans Ontarians, 35.1 % (95 % CI: 27.6, 42.5) seriously considered, and 11.2 % (95 % CI: 6.0, 16.4) attempted, suicide in the past year. Social support, reduced transphobia, and having any personal identification documents changed to an appropriate sex designation were associated with large relative and absolute reductions in suicide risk, as was completing a medical transition through hormones and/or surgeries (when needed). Parental support for gender identity was associated with reduced ideation. Lower self-reported transphobia (10(th) versus 90(th) percentile) was associated with a 66 % reduction in ideation (RR = 0.34, 95 % CI: 0.17, 0.67), and an additional 76 % reduction in attempts among those with ideation (RR = 0.24; 95 % CI: 0.07, 0.82). This corresponds to potential prevention of 160 ideations per 1000 trans persons, and 200 attempts per 1,000 with ideation, based on a hypothetical reduction of transphobia from current levels to the 10(th) percentile. CONCLUSIONS: Large effect sizes were observed for this controlled analysis of intervenable factors, suggesting that interventions to increase social inclusion and access to medical transition, and to reduce transphobia, have the potential to contribute to substantial reductions in the extremely high prevalences of suicide ideation and attempts within trans populations. Such interventions at the population level may require policy change.

The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors.

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that are critical to the regulation of excitatory synaptic function in the CNS. NMDARs govern experience-dependent synaptic plasticity and have been implicated in the pathophysiology of various neuropsychiatric disorders including the cognitive deficits of schizophrenia and certain forms of autism. Certain neurosteroids modulate NMDARs experimentally but their low potency, poor selectivity, and very low brain concentrations make them poor candidates as endogenous ligands or therapeutic agents. Here we show that the major brain-derived cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC) is a very potent, direct, and selective positive allosteric modulator of NMDARs with a mechanism that does not overlap that of other allosteric modulators. At submicromolar concentrations 24(S)-HC potentiates NMDAR-mediated EPSCs in rat hippocampal neurons but fails to affect AMPAR or GABAA receptors (GABA(A)Rs)-mediated responses. Cholesterol itself and other naturally occurring oxysterols present in brain do not modulate NMDARs at concentrations ≤10 µM. In hippocampal slices, 24(S)-HC enhances the ability of subthreshold stimuli to induce long-term potentiation (LTP). 24(S)-HC also reverses hippocampal LTP deficits induced by the NMDAR channel blocker ketamine. Finally, we show that synthetic drug-like derivatives of 24(S)-HC, which potently enhance NMDAR-mediated EPSCs and LTP, restore behavioral and cognitive deficits in rodents treated with NMDAR channel blockers. Thus, 24(S)-HC may function as an endogenous modulator of NMDARs acting at a novel oxysterol modulatory site that also represents a target for therapeutic drug development.

The Embryonic Transcriptome of the Red-Eared Slider Turtle (Trachemys scripta).

The bony shell of the turtle is an evolutionary novelty not found in any other group of animals, however, research into its formation has suggested that it has evolved through modification of conserved developmental mechanisms. Although these mechanisms have been extensively characterized in model organisms, the tools for characterizing them in non-model organisms such as turtles have been limited by a lack of genomic resources. We have used a next generation sequencing approach to generate and assemble a transcriptome from stage 14 and 17 Trachemys scripta embryos, stages during which important events in shell development are known to take place. The transcriptome consists of 231,876 sequences with an N50 of 1,166 bp. GO terms and EC codes were assigned to the 61,643 unique predicted proteins identified in the transcriptome sequences. All major GO categories and metabolic pathways are represented in the transcriptome. Transcriptome sequences were used to amplify several cDNA fragments designed for use as RNA in situ probes. One of these, BMP5, was hybridized to a T. scripta embryo and exhibits both conserved and novel expression patterns. The transcriptome sequences should be of broad use for understanding the evolution and development of the turtle shell and for annotating any future T. scripta genome sequences.

Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen.

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism, results from the transcriptional silencing of FMR1 and loss of the mRNA translational repressor protein fragile X mental retardation protein (FMRP). Patients with FXS exhibit changes in neuronal dendritic spine morphology, a pathology associated with altered synaptic function. Studies in the mouse model of fragile X have shown that loss of FMRP causes excessive synaptic protein synthesis, which results in synaptic dysfunction and altered spine morphology. We tested whether the pharmacologic activation of the γ-aminobutyric acid type B (GABA(B)) receptor could correct or reverse these phenotypes in Fmr1-knockout mice. Basal protein synthesis, which is elevated in the hippocampus of Fmr1-knockout mice, was corrected by the in vitro application of the selective GABA(B) receptor agonist STX209 (arbaclofen, R-baclofen). STX209 also reduced to wild-type values the elevated AMPA receptor internalization in Fmr1-knockout cultured neurons, a known functional consequence of increased protein synthesis. Acute administration of STX209 in vivo, at doses that modify behavior, decreased mRNA translation in the cortex of Fmr1-knockout mice. Finally, the chronic administration of STX209 in juvenile mice corrected the increased spine density in Fmr1-knockout mice without affecting spine density in wild-type mice. Thus, activation of the GABA(B) receptor with STX209 corrected synaptic abnormalities considered central to fragile X pathophysiology, a finding that suggests that STX209 may be a potentially effective therapy to treat the core symptoms of FXS.