Finasteride delays atherosclerosis progression in mice and is associated with a reduction in plasma cholesterol in men.

Finasteride is commonly prescribed to treat benign prostate hyperplasia and male-pattern baldness in cis men and, more recently, trans individuals. However, the effect of finasteride on cardiovascular disease remains elusive. We evaluated the role of finasteride on atherosclerosis using low-density lipoprotein (LDL) receptor-deficient (Ldlr-/-) mice. Next, we examined the relevance to humans by analyzing the data deposited between 2009 and 2016 in the National Health and Nutrition Examination Survey. We show that finasteride reduces total plasma cholesterol and delays the development of atherosclerosis in Ldlr-/- mice. Finasteride reduced monocytosis, monocyte recruitment to the lesion, macrophage lesion content, and necrotic core area, the latter of which is an indicator of plaque vulnerability in humans. RNA sequencing analysis revealed a downregulation of inflammatory pathways and an upregulation of bile acid metabolism, oxidative phosphorylation, and cholesterol pathways in the liver of mice taking finasteride. Men reporting the use of finasteride showed lower plasma levels of cholesterol and LDL-cholesterol than those not taking the drug. Our data unveil finasteride as a potential treatment to delay cardiovascular disease in people by improving the plasma lipid profile.

Sex differences in peripheral immune cell activation: Implications for pain and pain resolution.

Decades of research into chronic pain has deepened our understanding of the cellular mechanisms behind this process. However, a failure to consider the biological variable of sex has limited the application of these breakthroughs into clinical application. In the present study, we investigate fundamental differences in chronic pain between male and female mice resulting from inflammatory activation of the innate immune system. We provide evidence that female mice are more sensitive to the effects of macrophages. Injecting small volumes of media conditioned by either unstimulated macrophages or macrophages stimulated by the inflammatory molecule TNFα lead to increased pain sensitivity only in females. Interestingly, we find that TNFα conditioned media leads to a more rapid resolution of mechanical hypersensitivity and altered immune cell recruitment to sites of injury. Furthermore, male and female macrophages exhibit differential polarization characteristics and motility after TNFα stimulation, as well as a different profile of cytokine secretions. Finally, we find that the X-linked gene Tlr7 is critical in the facilitating the adaptive resolution of pain in models of acute and chronic inflammation in both sexes. Altogether, these findings suggest that although the cellular mechanisms of pain resolution may differ between the sexes, the study of these differences may yield more targeted approaches with clinical applications.

Assessing the landscape of STXBP1-related disorders in 534 individuals.

Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders is wide and clear correlations between variant type and clinical features have not been observed so far. Here, we harmonized clinical data across 534 individuals with STXBP1-related disorders and analysed 19 973 derived phenotypic terms, including phenotypes of 253 individuals previously unreported in the scientific literature. The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals, including focal-onset seizures as the most common seizure type (47%). More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life, including neonatal seizure onset in 47%. Individuals with protein-truncating variants and deletions in STXBP1 (n = 261) were almost twice as likely to present with West syndrome and were more phenotypically similar than expected by chance. Five genetic hotspots with recurrent variants were identified in more than 10 individuals, including p.Arg406Cys/His (n = 40), p.Arg292Cys/His/Leu/Pro (n = 30), p.Arg551Cys/Gly/His/Leu (n = 24), p.Pro139Leu (n = 12), and p.Arg190Trp (n = 11). None of the recurrent variants were significantly associated with distinct electroclinical syndromes, single phenotypic features, or showed overall clinical similarity, indicating that the baseline variability in STXBP1-related disorders is too high for discrete phenotypic subgroups to emerge. We then reconstructed the seizure history in 62 individuals with STXBP1-related disorders in detail, retrospectively assigning seizure type and seizure frequency monthly across 4433 time intervals, and retrieved 251 anti-seizure medication prescriptions from the electronic medical records. We demonstrate a dynamic pattern of seizure control and complex interplay with response to specific medications particularly in the first year of life when seizures in STXBP1-related disorders are the most prominent. Adrenocorticotropic hormone and phenobarbital were more likely to initially reduce seizure frequency in infantile spasms and focal seizures compared to other treatment options, while the ketogenic diet was most effective in maintaining seizure freedom. In summary, we demonstrate how the multidimensional spectrum of phenotypic features in STXBP1-related disorders can be assessed using a computational phenotype framework to facilitate the development of future precision-medicine approaches.

Anti-inflammatory role of GM1 and other gangliosides on microglia.

BACKGROUND: Gangliosides are glycosphingolipids highly enriched in the brain, with important roles in cell signaling, cell-to-cell communication, and immunomodulation. Genetic defects in the ganglioside biosynthetic pathway result in severe neurodegenerative diseases, while a partial decrease in the levels of specific gangliosides was reported in Parkinson's disease and Huntington's disease. In models of both diseases and other conditions, administration of GM1-one of the most abundant gangliosides in the brain-provides neuroprotection. Most studies have focused on the direct neuroprotective effects of gangliosides on neurons, but their role in other brain cells, in particular microglia, is not known. In this study we investigated the effects of exogenous ganglioside administration and modulation of endogenous ganglioside levels on the response of microglia to inflammatory stimuli, which often contributes to initiation or exacerbation of neurodegeneration. METHODS: In vitro studies were performed using BV2 cells, mouse, rat, and human primary microglia cultures. Modulation of microglial ganglioside levels was achieved by administration of exogenous gangliosides, or by treatment with GENZ-123346 and L-t-PDMP, an inhibitor and an activator of glycolipid biosynthesis, respectively. Response of microglia to inflammatory stimuli (LPS, IL-1ß, phagocytosis of latex beads) was measured by analysis of gene expression and/or secretion of pro-inflammatory cytokines. The effects of GM1 administration on microglia activation were also assessed in vivo in C57Bl/6 mice, following intraperitoneal injection of LPS. RESULTS: GM1 decreased inflammatory microglia responses in vitro and in vivo, even when administered after microglia activation. These anti-inflammatory effects depended on the presence of the sialic acid residue in the GM1 glycan headgroup and the presence of a lipid tail. Other gangliosides shared similar anti-inflammatory effects in in vitro models, including GD3, GD1a, GD1b, and GT1b. Conversely, GM3 and GQ1b displayed pro-inflammatory activity. The anti-inflammatory effects of GM1 and other gangliosides were partially reproduced by increasing endogenous ganglioside levels with L-t-PDMP, whereas inhibition of glycolipid biosynthesis exacerbated microglial activation in response to LPS stimulation. CONCLUSIONS: Our data suggest that gangliosides are important modulators of microglia inflammatory responses and reveal that administration of GM1 and other complex gangliosides exerts anti-inflammatory effects on microglia that could be exploited therapeutically.

Sex differences in kappa opioid receptor antinociception is influenced by the number of X chromosomes in mouse.

Kappa opioid receptor (KOR) agonists produce robust analgesia with minimal abuse liability and are considered promising pharmacological agents to manage chronic pain and itch. The KOR system is also notable for robust differences between the sexes, with females exhibiting lower analgesic response than males. Sexually dimorphic traits can be due to either the influence of gonadal hormones during development or adulthood, or due to the complement of genes expressed on the X or Y chromosome. Previous studies examining sex differences in KOR antinociception have relied on surgical or pharmacological manipulation of the gonads to determine whether sex hormones influence KOR function. While there are conflicting reports whether gonadal hormones influence KOR function, no study has examined these effects in context with sex chromosomes. Here, we use two genetic mouse models, the four core genotypes and XY*, to isolate the chromosomal and hormonal contributions to sex differences in KOR analgesia. Mice were treated with systemic KOR agonist (U50,488H) and thermal analgesia measured in the tail withdrawal assay. We found that KOR antinociception was influenced predominantly by the number of the X chromosomes. These data suggest that the dose and/or parental imprint on X gene(s) contribute significantly to the sexually dimorphism in KOR analgesia.

Genetic and functional analysis of a Pacific hagfish opioid system.

The actions of endogenous opioids and nociceptin/orphanin FQ are mediated by four homologous G protein-coupled receptors that constitute the opioid receptor family. However, little is known about opioid systems in cyclostomes (living jawless fish) and how opioid systems might have evolved from invertebrates. Here, we leveraged de novo transcriptome and low-coverage whole-genome assembly in the Pacific hagfish (Eptatretus stoutii) to identify and characterize the first full-length coding sequence for a functional opioid receptor in a cyclostome. Additionally, we define two novel endogenous opioid precursors in this species that predict several novel opioid peptides. Bioinformatic analysis shows no closely related opioid receptor genes in invertebrates with regard either to the genomic organization or to conserved opioid receptor-specific sequences that are common in all vertebrates. Furthermore, no proteins analogous to vertebrate opioid precursors could be identified by genomic searches despite previous claims of protein or RNA-derived sequences in several invertebrate species. The presence of an expressed orthologous receptor and opioid precursors in the Pacific hagfish confirms that a functional opioid system was likely present in the common ancestor of all extant vertebrates some 550 million years ago, earlier than all previous authenticated accounts. We discuss the premise that the cyclostome and vertebrate opioid systems evolved from invertebrate systems concerned with antimicrobial defense and speculate that the high concentrations of opioid precursors in tissues such as the testes, gut, and activated immune cells are key remnants of this evolutionary role.

Expanding the genotype and phenotype spectrum of SYT1-associated neurodevelopmental disorder.

PURPOSE: Synaptotagmin-1 (SYT1) is a critical mediator of neurotransmitter release in the central nervous system. Previously reported missense SYT1 variants in the C2B domain are associated with severe intellectual disability, movement disorders, behavioral disturbances, and electroencephalogram abnormalities. In this study, we expand the genotypes and phenotypes and identify discriminating features of this disorder. METHODS: We describe 22 individuals with 15 de novo missense SYT1 variants. The evidence for pathogenicity is discussed, including the American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria, known structure-function relationships, and molecular dynamics simulations. Quantitative behavioral data for 14 cases were compared with other monogenic neurodevelopmental disorders. RESULTS: Four variants were located in the C2A domain with the remainder in the C2B domain. We classified 6 variants as pathogenic, 4 as likely pathogenic, and 5 as variants of uncertain significance. Prevalent clinical phenotypes included delayed developmental milestones, abnormal eye physiology, movement disorders, and sleep disturbances. Discriminating behavioral characteristics were severity of motor and communication impairment, presence of motor stereotypies, and mood instability. CONCLUSION: Neurodevelopmental disorder-associated SYT1 variants extend beyond previously reported regions, and the phenotypic spectrum encompasses a broader range of severities than initially reported. This study guides the diagnosis and molecular understanding of this rare neurodevelopmental disorder and highlights a key role for SYT1 function in emotional regulation, motor control, and emergent cognitive function.

Drought stress increases the expression of barley defence genes with negative consequences for infesting cereal aphids.

Crops are exposed to myriad abiotic and biotic stressors with negative consequences. Two stressors that are expected to increase under climate change are drought and infestation with herbivorous insects, including important aphid species. Expanding our understanding of the impact drought has on the plant-aphid relationship will become increasingly important under future climate scenarios. Here we use a previously characterized plant-aphid system comprising a susceptible variety of barley, a wild relative of barley with partial aphid resistance, and the bird cherry-oat aphid to examine the drought-plant-aphid relationship. We show that drought has a negative effect on plant physiology and aphid fitness, and provide evidence to suggest that plant resistance influences aphid responses to drought stress. Furthermore, we show that the expression of thionin genes, plant defensive compounds that contribute to aphid resistance, increase in susceptible plants exposed to drought stress but remain at constant levels in the partially resistant plant, suggesting that they play an important role in determining the success of aphid populations. This study highlights the role of plant defensive processes in mediating the interactions between the environment, plants, and herbivorous insects.

Implementation of novel and conventional outbreak control measures in managing COVID-19 outbreaks in a large UK prison.

BACKGROUND: Outbreak control measures during COVID-19 outbreaks in a large UK prison consisted of standard (e.g., self-isolation) and novel measures, including establishment of: (i) reverse cohorting units for accommodating new prison admissions; (ii) protective isolation unit for isolating symptomatic prisoners, and (iii) a shielding unit to protect medically vulnerable prisoners. METHODS: Single-centre prospective longitudinal study (outbreak control study), implementing novel and traditional outbreak control measures to prevent a SARS-COV-2 outbreak. The prison held 977 prisoners and employed 910 staff at that start of the outbreak. RESULTS: 120 probable and 25 confirmed cases among prisoners and staff were recorded between March and June 2020 during the first outbreak. Over 50% of initial cases among prisoners were on the two wings associated with the index case. During the second outbreak, 182 confirmed cases were recorded after probable reintroduction from a staff member. Widespread testing identified 145 asymptomatic prisoners, 16.9% of the total prisoner cases. The cohorting units prevented re-infection from new prison admissions and the shielding unit had no COVID-19 infections linked to either outbreak. CONCLUSIONS: Identifying and isolating infected prisoners, cohorting new admissions and shielding vulnerable individuals helped prevent uncontrollable spread of SARS-COV-2. These novel and cost-effective approaches can be implemented in correctional facilities globally.

Recommendations for improving the working conditions and cultures of distressed junior doctors, based on a qualitative study and stakeholder perspectives.

BACKGROUND: Doctors, including junior doctors, are vulnerable to greater levels of distress and mental health difficulties than the public. This is exacerbated by their working conditions and cultures. While this vulnerability has been known for many years, little action has been taken to protect and support junior doctors working in the NHS. As such, we present a series of recommendations from the perspective of junior doctors and other relevant stakeholders, designed to improve junior doctors' working conditions and, thus, their mental health. METHODS: We interviewed 36 junior doctors, asking them for recommendations for improving their working conditions and culture. Additionally, we held an online stakeholder meeting with a variety of healthcare professionals (including junior doctors), undergraduate medical school leads, postgraduate speciality school leads and NHS policymakers where we asked what could be done to improve junior doctors' working conditions. We combined interview data with notes from the stakeholder discussions to produce this set of recommendations. RESULTS: Junior doctor participants and stakeholders made organisational and interpersonal recommendations. Organisational recommendations include the need for more environmental, staff and educational resources as well as changes to rotas. Interpersonal recommendations include changes to communication and recommendations for better support and teamwork. CONCLUSION: We suggest that NHS policymakers, employers and managers consider and hopefully implement the recommendations set out by the study participants and stakeholders as reported in this paper and that the gold standards of practice which are reported here (such as examples of positive learning environments and supportive supervision) are showcased so that others can learn from them.

'Reluctant pioneer': A qualitative study of doctors' experiences as patients with long COVID.

BACKGROUND: The coronavirus disease (COVID-19) pandemic has had far-reaching effects upon lives, healthcare systems and society. Some who had an apparently 'mild' COVID-19 infection continue to suffer from persistent symptoms, including chest pain, breathlessness, fatigue, cognitive impairment, paraesthesia, muscle and joint pains. This has been labelled 'long COVID'. This paper reports the experiences of doctors with long COVID. METHODS: A qualitative study; interviews with doctors experiencing persistent symptoms were conducted by telephone or video call. Interviews were transcribed and analysis conducted using an inductive and thematic approach. RESULTS: Thirteen doctors participated. The following themes are reported: making sense of symptoms, feeling let down, using medical knowledge and connections, wanting to help and be helped, combining patient and professional identity. Experiencing long COVID can be transformative: many expressed hope that good would come of their experiences. Distress related to feelings of being 'let down' and the hard work of trying to access care. Participants highlighted that they felt better able to care for, and empathize with, patients with chronic conditions, particularly where symptoms are unexplained. CONCLUSIONS: The study adds to the literature on the experiences of doctors as patients, in particular where evidence is emerging and the patient has to take the lead in finding solutions to their problems and accessing their own care. PATIENT AND PUBLIC CONTRIBUTION: The study was developed with experts by experience (including co-authors HA and TAB) who contributed to the protocol and ethics application, and commented on analysis and implications. All participants were given the opportunity to comment on findings.

Kappa Opioid Receptors Drive a Tonic Aversive Component of Chronic Pain.

Pain is a multidimensional experience and negative affect, or how much the pain is "bothersome", significantly impacts the sufferers' quality of life. It is well established that the κ opioid system contributes to depressive and dysphoric states, but whether this system contributes to the negative affect precipitated by the occurrence of chronic pain remains tenuous. Using a model of persistent pain, we show by quantitative real-time-PCR, florescence in situ hybridization, Western blotting and GTPgS autoradiography an upregulation of expression and the function of κ opioid receptors (KORs) and its endogenous ligand dynorphin in the mesolimbic circuitry in animals with chronic pain compared with surgical controls. Using in vivo microdialysis and microinjection of drugs into the mesolimbic dopamine system, we demonstrate that inhibiting KORs reinstates evoked dopamine release and reward-related behaviors in chronic pain animals. Chronic pain enhanced KOR agonist-induced place aversion in a sex-dependent manner. Using various place preference paradigms, we show that activation of KORs drives pain aversive states in male but not female mice. However, KOR antagonist treatment was effective in alleviating anxiogenic and depressive affective-like behaviors in both sexes. Finally, ablation of KORs from dopamine neurons using AAV-TH-cre in KORloxP mice prevented pain-induced aversive states as measured by place aversion assays. Our results strongly support the use of KOR antagonists as therapeutic adjuvants to alleviate the emotional, tonic-aversive component of chronic pain, which is argued to be the most significant component of the pain experience that impacts patients' quality of life.SIGNIFICANCE STATEMENT We show that KORs are sufficient to drive the tonic-aversive component of chronic pain; the emotional component of pain that is argued to significantly impact a patient's quality of life. The impact of our study is broadly relevant to affective disorders associated with disruption of reward circuitry and thus likely contributes to many of the devastating sequelae of chronic pain, including the poor response to treatment of many patients, debilitating affective disorders (other disorders including anxiety and depression that demonstrate high comorbidity with chronic pain) and substance abuse. Indeed, coexisting psychopathology increases pain intensity, pain-related disability and effectiveness of treatments (Jamison and Edwards, 2013).

Pain, Motivation, Migraine, and the Microbiome: New Frontiers for Opioid Systems and Disease.

For decades the broad role of opioids in addiction, neuropsychiatric disorders, and pain states has been somewhat well established. However, in recent years, with the rise of technological advances, not only is the existing dogma being challenged, but we are identifying new disease areas in which opioids play a critical role. This review highlights four new areas of exploration in the opioid field. The most recent addition to the opioid family, the nociceptin receptor system, shows promise as the missing link in understanding the neurocircuitry of motivation. It is well known that activation of the kappa opioid receptor system modulates negative affect and dysphoria, but recent studies now implicate the kappa opioid system in the modulation of negative affect associated with pain. Opioids are critical in pain management; however, the often-forgotten delta opioid receptor system has been identified as a novel therapeutic target for headache disorders and migraine. Lastly, changes to the gut microbiome have been shown to directly contribute to many of the symptoms of chronic opioid use and opioid related behaviors. This review summarizes the findings from each of these areas with an emphasis on identifying new therapeutic targets. SIGNIFICANCE STATEMENT: The focus of this minireview is to highlight new disease areas or new aspects of disease in which opioids have been implicated; this includes pain, motivation, migraine, and the microbiome. In some cases, this has resulted in the pursuit of a novel therapeutic target and resultant clinical trial. We believe this is very timely and will be a refreshing take on reading about opioids and disease.

Ontogenesis and Modulation of Intestinal Unesterified Cholesterol Sequestration in a Mouse Model of Niemann-Pick C1 Disease.

BACKGROUND: Mutations in the NPC1 gene result in sequestration of unesterified cholesterol (UC) and glycosphingolipids in most tissues leading to multi-organ disease, especially in the brain, liver, lungs, and spleen. Various data from NPC1-deficient mice suggest the small intestine (SI) is comparatively less affected, even in late stage disease. METHODS: Using the Npc1nih mouse model, we measured SI weights and total cholesterol (TC) levels in Npc1-/- versus Npc1+/+ mice as a function of age, and then after prolonged ezetimibe-induced inhibition of cholesterol absorption. Next, we determined intestinal levels of UC and esterified cholesterol (EC), and cholesterol synthesis rates in Npc1-/- and Npc1+/+ mice, with and without the cholesterol-esterifying enzyme SOAT2, following a once-only subcutaneous injection with 2-hydroxypropyl-ß-cyclodextrin (2HPßCD). RESULTS: By ~ 42 days of age, intestinal TC levels averaged ~ 2.1-fold more (mostly UC) in the Npc1-/- versus Npc1+/+ mice with no further increase thereafter. Chronic ezetimibe treatment lowered intestinal TC levels in the Npc1-/- mice by only ~ 16%. In Npc1-/- mice given 2HPßCD 24 h earlier, UC levels fell, EC levels increased (although less so in mice lacking SOAT2), and cholesterol synthesis was suppressed equally in the Npc1-/-:Soat2+/+ and Npc1-/-:Soat2-/- mice. CONCLUSIONS: The low and static levels of intestinal UC sequestration in Npc1-/- mice likely reflect the continual sloughing of cells from the mucosa. This sequestration is blunted by about the same extent following a single acute treatment with 2HPßCD as it is by a prolonged ezetimibe-induced block of cholesterol absorption.

Digital Interventions for Screening and Treating Common Mental Disorders or Symptoms of Common Mental Illness in Adults: Systematic Review and Meta-analysis.

BACKGROUND: Digital interventions targeting common mental disorders (CMDs) or symptoms of CMDs are growing rapidly and gaining popularity, probably in response to the increased prevalence of CMDs and better awareness of early help-seeking and self-care. However, no previous systematic reviews that focus on these novel interventions were found. OBJECTIVE: This systematic review aims to scope entirely web-based interventions that provided screening and signposting for treatment, including self-management strategies, for people with CMDs or subthreshold symptoms. In addition, a meta-analysis was conducted to evaluate the effectiveness of these interventions for mental well-being and mental health outcomes. METHODS: Ten electronic databases including MEDLINE, PsycINFO, and EMBASE were searched from January 1, 1999, to early April 2020. We included randomized controlled trials (RCTs) that evaluated a digital intervention (1) targeting adults with symptoms of CMDs, (2) providing both screening and signposting to other resources including self-care, and (3) delivered entirely through the internet. Intervention characteristics including target population, platform used, key design features, and outcome measure results were extracted and compared. Trial outcome results were included in a meta-analysis on the effectiveness of users' well-being and mental health outcomes. We also rated the meta-analysis results with the Grading of Recommendations, Assessment, Development, and Evaluations approach to establish the quality of the evidence. RESULTS: The electronic searches yielded 21 papers describing 16 discrete digital interventions. These interventions were investigated in 19 unique trials including 1 (5%) health economic study. Most studies were conducted in Australia and North America. The targeted populations varied from the general population to allied health professionals. All interventions offered algorithm-driven screening with measures to assess symptom levels and to assign treatment options including automatic web-based psychoeducation, self-care strategies, and signposting to existing services. A meta-analysis of usable trial data showed that digital interventions improved well-being (3 randomized controlled trials [RCTs]; n=1307; standardized mean difference [SMD] 0.40; 95% CI 0.29 to 0.51; I2=28%; fixed effect), symptoms of mental illness (6 RCTs; n=992; SMD -0.29; 95% CI -0.49 to -0.09; I2=51%; random effects), and work and social functioning (3 RCTs; n=795; SMD -0.16; 95% CI -0.30 to -0.02; I2=0%; fixed effect) compared with waitlist or attention control. However, some follow-up data failed to show any sustained effects beyond the post intervention time point. Data on mechanisms of change and cost-effectiveness were also lacking, precluding further analysis. CONCLUSIONS: Digital mental health interventions to assess and signpost people experiencing symptoms of CMDs appear to be acceptable to a sufficient number of people and appear to have enough evidence for effectiveness to warrant further study. We recommend that future studies incorporate economic analysis and process evaluation to assess the mechanisms of action and cost-effectiveness to aid scaling of the implementation.

Assessing Postsecondary Barriers for Rural Appalachian High School Students.

Social cognitive career theory indicates that perceived barriers negatively affect career and educational self-efficacy beliefs and may also impact interests, goals, and actions. However, measurement of barriers has produced mixed results, and few quantitative studies explore the perceived barriers of rural Appalachian students. In this series of studies, we explored the perceived educational and career barriers of rural Appalachian high school students. Our goal was to identify perceived barriers, but as initial results were analyzed, we then shifted to how best to measure barriers and how culture impacted the reporting of barriers by rural Appalachian students. The results of our mixed-method series of studies offer ideas on how cultural values and beliefs may skew reporting of contextual influences on career and education.

Stress reactivity after traumatic brain injury: implications for comorbid post-traumatic stress disorder.

Most people have or will experience traumatic stress at some time over the lifespan, but only a subset of traumatized individuals develop post-traumatic stress disorder (PTSD). Clinical research supports high rates of traumatic brain injury (TBI)-PTSD comorbidity and demonstrates TBI as a significant predictor of the development of PTSD. Biological factors impacted following brain injury that may contribute to increased PTSD risk are unknown. Heightened stress reactivity and dysregulated hypothalamic-pituitary-adrenal (HPA) axis function are common to both TBI and PTSD, and affect amygdalar structure and function, which is implicated in PTSD. In this review, we summarize a growing body of literature that shows HPA axis dysregulation, as well as enhanced fear and amygdalar function after TBI. We present the hypothesis that altered stress reactivity as a result of brain injury impacts the amygdala and defense systems to be vulnerable to increased fear and PTSD development from traumatic stress. Identifying biological mechanisms that underlie this vulnerability, such as dysregulated HPA axis function, may lead to better targeted treatments and preventive measures to support psychological health after TBI.

Development and Evaluation of a Recovery College Fidelity Measure.

OBJECTIVE: Recovery Colleges are widespread, with little empirical research on their key components. This study aimed to characterize key components of Recovery Colleges and to develop and evaluate a developmental checklist and a quantitative fidelity measure. METHODS: Key components were identified through a systematized literature review, international expert consultation (n = 77), and semistructured interviews with Recovery College managers across England (n = 10). A checklist was developed and refined through semistructured interviews with Recovery College students, trainers, and managers (n = 44) in 3 sites. A fidelity measure was adapted from the checklist and evaluated with Recovery College managers (n = 39, 52%), clinicians providing psychoeducational courses (n = 11), and adult education lecturers (n = 10). RESULTS: Twelve components were identified, comprising 7 nonmodifiable components (Valuing Equality, Learning, Tailored to the Student, Coproduction of the Recovery College, Social Connectedness, Community Focus, and Commitment to Recovery) and 5 modifiable components (Available to All, Location, Distinctiveness of Course Content, Strengths Based, and Progressive). The checklist has service user student, peer trainer, and manager versions. The fidelity measure meets scaling assumptions and demonstrates adequate internal consistency (0.72), test-retest reliability (0.60), content validity, and discriminant validity. CONCLUSIONS: Coproduction and an orientation to adult learning should be the highest priority in developing Recovery Colleges. The creation of the first theory-based empirically evaluated developmental checklist and fidelity measure (both downloadable at researchintorecovery.com/recollect ) for Recovery Colleges will help service users understand what Recovery Colleges offer, will inform decision making by clinicians and commissioners about Recovery Colleges, and will enable formal evaluation of their impact on students.

Early and Late Loss of the Cytoskeletal Scaffolding Protein, Ankyrin G Reveals Its Role in Maturation and Maintenance of Nodes of Ranvier in Myelinated Axons.

The mechanisms that govern node of Ranvier organization, stability, and long-term maintenance remain to be fully elucidated. One of the molecular components of the node is the cytoskeletal scaffolding protein, ankyrin G (AnkG), which interacts with multiple members of the nodal complex. The role of AnkG in nodal organization and maintenance is still not clearly defined as to whether AnkG functions as an initial nodal organizer or whether it functions as a nodal stabilizer after the nodal complex has been assembled. Using a mouse model system, we report here that perinatal and juvenile neuronal ablation of AnkG has differential consequences on nodal stability. Early loss of AnkG creates immature nodes with abnormal morphology, which undergo accelerated destabilization within a month, resulting in rapid voltage-gated sodium (NaV) channel and ßIV spectrin loss with reduced effects on neurofascin 186. On the other hand, late ablation of AnkG from established nodal complexes leads to slow but progressive nodal destabilization over 10 months, primarily affecting ßIV spectrin, followed by NaV channels, with modest impact on neurofascin 186. We also show that ankyrin R and ßI spectrin are not sufficient to prevent nodal disorganization after AnkG ablation. Additionally, nodal disorganization in both early and late AnkG mutants is accompanied by axonal pathology and neurological dysfunction. Together, our results suggest that AnkG plays an indispensable role in the maturation and long-term stabilization of the newly assembled nodal complex, and that loss of AnkG after nodal stabilization does not lead to rapid nodal disassembly but to loss of specific nodal components in a time-dependent manner.SIGNIFICANCE STATEMENT Nodes of Ranvier are the myelin-free gaps along myelinated axons that allow fast communication between neurons and their target cells by propagating action potentials in a saltatory manner. The cytoskeletal scaffolding protein ankyrin G (AnkG) has been thought to play an important role in node formation; however, its precise role in nodal assembly, stability, and maintenance is still not clear. By using spatiotemporal ablation of AnkG, we report its differential role in nodal maturation and stabilization. We show that early AnkG-deficient nodes fail to mature and undergo rapid destabilization. In contrast, nodes that assemble with AnkG are much more stable and undergo gradual disintegration with sequential loss of nodal components in the absence of AnkG.

Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability.

Myelinated axons segregate the axonal membrane into four defined regions: the node of Ranvier, paranode, juxtaparanode, and internode. The paranodal junction consists of specific component proteins, such as neurofascin155 (NF155) on the glial side, and Caspr and Contactin on the axonal side. Although paranodal junctions are thought to play crucial roles in rapid saltatory conduction and nodal assembly, the role of their interaction with neurons is not fully understood. In a previous study, conditional NF155 knockout in oligodendrocytes led to disorganization of the paranodal junctions. To examine if disruption of paranodal junctions affects neuronal gene expression, we prepared total RNA from the retina of NF155 conditional knockout, and performed expression analysis. We found that the expression level of 433 genes changed in response to paranodal junction ablation. Interestingly, expression of aquaporin 3 (AQP3) was significantly reduced in NF155 conditional knockout mice, but not in cerebroside sulfotransferase knockout (CST-KO) mice, whose paranodes are not originally formed during development. Copy number variations have an important role in the etiology of schizophrenia (SCZ). We observed rare duplications of AQP3 in SCZ patients, suggesting a correlation between abnormal AQP3 expression and SCZ. To determine if AQP3 over-expression in NF155 conditional knockout mice influences neuronal function, we performed adeno-associated virus (AAV)-mediated over-expression of AQP3 in the motor cortex of mice and found a significant increase in caspase 3-dependent neuronal apoptosis in AQP3-transduced cells. This study may provide new insights into therapeutic approaches for SCZ by regulating AQP3 expression, which is associated with paranodal disruption.