Mutations causing syndromic autism define an axis of synaptic pathophysiology

Tuberous sclerosis complex and fragile X syndrome are genetic diseases characterized by intellectual disability and autism. Because both syndromes are caused by mutations in genes that regulate protein synthesis in neurons, it has been hypothesized that excessive protein synthesis is one core pathophysiological mechanism of intellectual disability and autism. Using electrophysiological and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2+/− and Fmr1−/y mice, here we show that synaptic dysfunction caused by these mutations actually falls at opposite ends of a physiological spectrum. Synaptic, biochemical and cognitive defects in these mutants are corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions, and deficits in the mutants disappear when the mice are bred to carry both mutations. Thus, normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate-receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioural impairments.National Institute of Mental Health (U.S.) (T32 MH-082718)National Institute of Mental Health (U.S.) (T32-MH-074249)Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (2R01HD046943)United States. Dept. of Defense (W81XWH-11-1-0252)Simons Foundatio

Obligatory Role of NR2A for Metaplasticity in Visual Cortex

Light deprivation lowers the threshold for long-term depression (LTD) and long-term potentiation (LTP) in visual cortex by a process termed metaplasticity, but the mechanism is unknown. The decreased LTD/P threshold correlates with a decrease in the ratio of NR2A to NR2B subunits of cortical NMDA receptors (NMDARs) and a slowing of NMDAR-mediated excitatory postsynaptic currents (EPSCs). However, whether and how changes in NR2 subunit expression contribute to LTD and LTP remains controversial. In the present study, we used an NR2A knockout (KO) mouse to examine the role of this subunit in the experience-dependent modulation of NMDAR properties, LTD, and LTP. In wild-type (WT) mice, we found what has previously been shown in rats, that dark rearing alters NMDAR EPSC kinetics and temporal summation, LTP, and LTD in layer 2/3 of visual cortex. Deletion of NR2A mimicked the effect of dark-rearing on NMDAR EPSCs, and there was no additional effect of dark-rearing in the NR2A KO mice. Thus, deletion of NR2A abrogates the effects of visual experience on NMDAR EPSCs. Moreover, metaplasticity of LTP and LTD was completely lost in the absence of NR2A. These data support the hypothesis that experience-dependent changes in NR2A/B are functionally significant and yield a mechanism for an adjustable synaptic modification threshold in visual cortex

Exploring Referral and Service Utilization Patterns Within an Outpatient Interdisciplinary Pediatric Chronic Pain Program

PURPOSE: We examine referral sources and clinical characteristics for youth presenting to an outpatient interdisciplinary pediatric chronic pain program. PATIENTS AND METHODS: Referral data were extracted from the electronic health record. PROMIS Pediatric Anxiety and Pain Interference Scales were administered at an initial evaluation visit. RESULTS: The program received 1488 referrals between 2016 and 2019, representing 1338 patients, with increasing volume of referrals over time. Referrals were primarily from orthopedics (19.6%), physical medicine and rehabilitation (18.8%), neurology (14.4%), and rheumatology (12.6%). Patients referred were primarily female (75.4%), White (80.1%), English-speaking (98.4%) adolescents (median=15.0 years). Of those referred, 732 (54.7%) attended an interdisciplinary evaluation (ie, with ≥2 disciplines). Adolescent anxiety was within the expected range by self-report (N=327, M CONCLUSION: Results highlight the demand for outpatient interdisciplinary pediatric chronic pain treatment. Findings can inform decisions related to staffing and service design for pediatric hospitals that aim to establish or grow outpatient pediatric chronic pain programs

Experiences with Menses in Transgender and Gender Nonbinary Adolescents.

STUDY OBJECTIVE: To describe menstrual history, associated dysphoria, and desire for menstrual management in transgender male and gender diverse adolescents who were assigned female at birth DESIGN: Retrospective chart review SETTING: Tertiary care children\u27s hospital PARTICIPANTS: All patients seen in a multidisciplinary pediatric gender program from March 2015 through December 2020 who were assigned female at birth, identified as transgender male or gender nonbinary, and had achieved menarche INTERVENTION: None MAIN OUTCOME MEASURES: Patient demographics, menstrual history, interest in and prior experiences with menstrual management, parental support, and concerns about menstrual management RESULTS: Of the 129 included patients, 116 (90%) identified as transgender male and 13 (10%) as gender nonbinary, with an average age of 15 (SD 1.6) years. Almost all (93%) patients reported menstrual-related dysphoria. Most (88%) were interested in menstrual suppression. The most common reasons for desiring suppression were achievement of amenorrhea (97%) and improvement of menstrual-related dysphoria (63%). CONCLUSIONS: Most gender diverse patients assigned female at birth reported dysphoria associated with menses and desired menstrual suppression. This information can encourage physicians to raise this topic and offer menstrual management for gender diverse patients who experience distress related to menses, especially for those who are not ready for or do not desire gender-affirming hormonal treatment. Future research is needed to better understand patients\u27 experiences with menses and to determine the optimal menstrual management methods. This could be an important intervention to improve outcomes for this vulnerable population

Effects of Heart Rate and Ventricular Wall Thickness on Non-invasive Mapping: An in silico Study

Background: Non-invasive cardiac mapping—also known as Electrocardiographic imaging (ECGi)—is a novel, painless and relatively economic method to map the electrical activation and repolarization patterns of the heart, providing a valuable tool for early identification and diagnosis of conduction abnormalities and arrhythmias. Moreover, the ability to obtain information on cardiac electrical activity non-invasively using ECGi provides the potential for a priori information to guide invasive surgical procedures, improving success rates, and reducing procedure time. Previous studies have shown the influence of clinical variables, such as heart rate, heart size, endocardial wall, and body composition on surface electrocardiogram (ECG) measurements. The influence of clinical variables on the ECG variability has provided information on cardiovascular control and its abnormalities in various pathologies. However, the effects of such clinical variables on the Body Surface Potential (BSP) and ECGi maps have yet to be systematically investigated. Methods: In this study we investigated the effects of heart size, intracardiac thickness, and heart rate on BSP and ECGi maps using a previously-developed 3D electrophysiologically-detailed ventricles-torso model. The inverse solution was solved using the three different Tikhonov regularization methods. Results: Through comparison of multiple measures of error/accuracy on the ECGi reconstructions, our results showed that using different heart geometries to solve the forward and inverse problems produced a larger estimated focal excitation location. An increase of ~2 mm in the Euclidean distance error was observed for an increase in the heart size. However, the estimation of the location of focal activity was still able to be obtained. Similarly, a Euclidean distance increase was observed when the order of regularization was reduced. For the case of activation maps reconstructed at the same ectopic focus location but different heart rates, an increase in the errors and Euclidean distance was observed when the heart rate was increased. Conclusions: Non-invasive cardiac mapping can still provide useful information about cardiac activation patterns for the cases when a different geometry is used for the inverse problem compared to the one used for the forward solution; rapid pacing rates can induce order-dependent errors in the accuracy of reconstruction

Correction of fragile X syndrome in mice

SummaryFragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders

Menstrual management in adolescent transgender males

Introduction: Gender dysphoria is associated with increased rates of anxiety, depression, and suicidal ideation in adolescents. There is anecdotal evidence that menstruation increases the occurrence of gender dysphoria in adolescent transgender males. We hypothesize that menses are distressing to transgender males and this population would benefit from menstrual management. Methods: We conducted a retrospective chart review of all transgender male patients seen in the Nemours Gender Wellness Program (GWP) and limited our population to those who have reached menarche. Data was extracted from the encounters at the GWP clinic and recorded in REDCap. We compared self-reported symptoms of gender dysphoria at 3 months, 6 months, and one year following an individual’s baseline visit to the GWP. The incidence of gender dysphoria at subsequent visits will highlight the efficacy of treatment. Results: Preliminary results show that a majority of our population reported significant gender dysphoria related to menses. Of patients reporting gender dysphoria at the initial visit, 84% chose to use menstrual suppression. Patients who chose an IUD at the initial visit had a higher incidence of breakthrough bleeding and gender dysphoria at the first follow up visit compared to patients who chose other menstrual suppression methods. Conclusion: Menstruation is associated with increased gender dysphoria in transgender male adolescents. Menstrual suppression has the potential to be a transformative treatment for this population. Further research is necessary to determine whether the potential harm that could result from prolonging the distress associated with menses justifies the benefits of using an IUD

A fully coupled hydro-mechanical model for the modeling of coalbed methane recovery

Most coal seams hold important quantities of methane which is recognized as a valuable energy resource. Coal reservoir is considered not conventional because methane is held adsorbed on the coal surface. Coal is naturally fractured, it is a dual-porosity system made of matrix blocks and cleats (i.e fractures). In general, cleats are initially water saturated with the hydrostatic pressure maintaining the gas adsorbed in the coal matrix. Production of coalbed methane (CBM) first requires the mobilization of water in the cleats to reduce the reservoir pressure. Changes of coal properties during methane production are a critical issue in coalbed methane recovery. Indeed, any change of the cleat network will likely translate into modifications of the reservoir permeability. This work consists in the formulation of a consistent hydro-mechanical model for the CBM production modeling. Due to the particular structure of coal, the model is based on a dual-continuum approach to enrich the macroscale with microscale considerations. Shape factors are employed to take into account the geometry of the matrix blocks in the mass exchange between matrix and fractures. The hydro-mechanical model is fully coupled. For example, it captures the sorption-induced volumetric strain or the dependence of permeability on fracture aperture, which evolves with the stress state. The model is implemented in the finite element code Lagamine and is used for the modeling of one production well. A synthetic reservoir and then a real production case are considered. To date, attention has focused on a series of parametric analyses that can highlight the influence of the production scenario or key parameters related to the reservoir

International Nonregimes: A Research Agenda1

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146934/1/j.1468-2486.2007.00672.x.pd