An open label pilot trial of low-dose lithium for young people at ultra-high risk for psychosis.

AIM: Lithium, even at low doses, appears to offer neuroprotection against a wide variety of insults. In this controlled pilot, we examined the safety (i.e., side-effect profile) of lithium in a sample of young people identified at ultra-high risk (UHR) for psychosis. The secondary aim was to explore whether lithium provided a signal of clinical efficacy in reducing transition to psychosis compared with treatment as usual (TAU). METHODS: Young people attending the PACE clinic at Orygen, Melbourne, were prescribed a fixed dose (450 mg) of lithium (n = 25) or received TAU (n = 78). The primary outcome examined side-effects, with transition to psychosis, functioning and measures of psychopathology assessed as secondary outcomes. RESULTS: Participants in both groups were functionally compromised (lithium group GAF = 56.6; monitoring group GAF = 56.9). Side-effect assessment indicated that lithium was well-tolerated. 64% (n = 16) of participants in the lithium group were lithium-adherent to week 12. Few cases transitioned to psychosis across the study period; lithium group 4% (n = 1); monitoring group 7.7% (n = 6). There was no difference in time to transition to psychosis between the groups. No group differences were observed in other functioning and symptom domains, although all outcomes improved over time. CONCLUSIONS: With a side-effect profile either comparable to, or better than UHR antipsychotic trials, lithium might be explored for further research with UHR young people. A definitive larger trial is needed to determine the efficacy of lithium in this cohort.

CyclinD2-mediated regulation of neurogenic output from the retinal ciliary margin is perturbed in albinism.

In albinism, aberrations in the ipsi-/contralateral retinal ganglion cell (RGC) ratio compromise the functional integrity of the binocular circuit. Here, we focus on the mouse ciliary margin zone (CMZ), a neurogenic niche at the embryonic peripheral retina, to investigate developmental processes regulating RGC neurogenesis and identity acquisition. We found that the mouse ventral CMZ generates predominantly ipsilaterally projecting RGCs, but this output is altered in the albino visual system because of CyclinD2 downregulation and disturbed timing of the cell cycle. Consequently, albino as well as CyclinD2-deficient pigmented mice exhibit diminished ipsilateral retinogeniculate projection and poor depth perception. In albino mice, pharmacological stimulation of calcium channels, known to upregulate CyclinD2 in other cell types, augmented CyclinD2-dependent neurogenesis of ipsilateral RGCs and improved stereopsis. Together, these results implicate CMZ neurogenesis and its regulators as critical for the formation and function of the mammalian binocular circuit.

Role for a Web-Based Intervention to Alleviate Distress in People With Newly Diagnosed Testicular Cancer: Mixed Methods Study.

BACKGROUND: Distress is common immediately after diagnosis of testicular cancer. It has historically been difficult to engage people in care models to alleviate distress because of complex factors, including differential coping strategies and influences of social gender norms. Existing support specifically focuses on long-term survivors of testicular cancer, leaving an unmet need for age-appropriate and sex-sensitized support for individuals with distress shortly after diagnosis. OBJECTIVE: We evaluated a web-based intervention, Nuts & Bolts, designed to provide support and alleviate distress after diagnosis of testicular cancer. METHODS: Using a mixed methods design to evaluate the acceptability, feasibility, and impact of Nuts & Bolts on distress, we randomly assigned participants with recently diagnosed testicular cancer (1:1) access to Nuts & Bolts at the time of consent (early) or alternatively, 1 week later (day 8; delayed). Participants completed serial questionnaires across a 4- to 5-week period to evaluate levels of distress (measured by the National Comprehensive Cancer Network Distress Thermometer [DT]; scored 0-10), anxiety, and depression (Hospital Anxiety and Depression Score [HADS]-Anxiety and HADS-Depression; each scored 0-21). The primary end point was change in distress between consent and day 8. Secondary end points of distress, anxiety, and depression were assessed at defined intervals during follow-up. Optional, semistructured interviews occurring after completion of quantitative assessments were thematically analyzed. RESULTS: Overall, 39 participants were enrolled in this study. The median time from orchidectomy to study consent was 14.8 (range 3-62) days. Moderate or high levels of distress evaluated using DT were reported in 58% (23/39) of participants at consent and reduced to 13% (5/38) after 1 week of observation. Early intervention with Nuts & Bolts did not significantly decrease the mean DT score by day 8 compared with delayed intervention (early: 4.56-2.74 vs delayed: 4.47-2.74; P=.85), who did not yet have access to the website. A higher baseline DT score was significantly predictive of reduction in DT score during this period (P<.001). Median DT, HADS-Anxiety, and HADS-Depression scores reduced between orchidectomy and 3 weeks postoperatively and then remained stable throughout the observation period. Thematic analysis of 16 semistructured interviews revealed 4 key themes, "Nuts & Bolts is a helpful tool," "Maximizing benefits of the website," "Whirlwind of diagnosis and readiness for treatment," and "Primary stressors and worries," as well as multiple subthemes. CONCLUSIONS: Distress is common following the diagnosis of testicular cancer; however, it decreases over time. Nuts & Bolts was considered useful, acceptable, and relevant by individuals diagnosed with testicular cancer, with strong support for the intervention rendered by thematic analyses of semistructured interviews. The best time to introduce support, such as Nuts & Bolts, is yet to be determined; however, it may be most beneficial as soon as testicular cancer is strongly suspected or diagnosed.

Translating Psychedelic Therapies From Clinical Trials to Community Clinics: Building Bridges and Addressing Potential Challenges Ahead.

Research exploring the potential of psychedelic-assisted therapies to treat a range of mental illnesses is flourishing, after the problematic sociopolitical history of psychedelics led to the shutdown of clinical research for almost 40 years. Encouraged by positive results, clinicians and patients are now hopeful that further interruptions to research will be avoided, so that the early promise of these therapies might be fulfilled. At this early stage of renewed interest, researchers are understandably focusing more on clinical trials to investigate safety and efficacy, than on longer-term goals such as progression to community practice. Looking to identify and avoid potential pitfalls on the path to community clinics, the authors, a group of Australian clinicians and researchers, met to discuss possible obstacles. Five broad categories of challenge were identified: 1) inherent risks; 2) poor clinical practice; 3) inadequate infrastructure; 4) problematic perceptions; and 5) divisive relationships and fractionation of the field. Our analysis led us to propose some strategies, including public sector support of research and training to establish best practice and optimize translation, and funding to address issues of equitable access to treatment. Above all, we believe that strategic planning and professional cohesion will be crucial for success. Accordingly, our key recommendation is the establishment of a multidisciplinary advisory body, broadly endorsed and representing all major stakeholders, to guide policy and implementation of psychedelic-assisted therapies in Australia. Although these challenges and strategies are framed within the Australian context, we sense that they may generalize to other parts of the world. Wherever they apply, we believe that anticipation of potential difficulties, and creative responses to address them, will be important to avoid roadblocks in the future and keep the "psychedelic renaissance" on track.

Unraveling the complex genetics of neural tube defects: From biological models to human genomics and back.

Neural tube defects (NTDs) are a classic example of preventable birth defects for which there is a proven-effective intervention, folic acid (FA); however, further methods of prevention remain unrealized. In the decades following implementation of FA nutritional fortification programs throughout at least 87 nations, it has become apparent that not all NTDs can be prevented by FA. In the United States, FA fortification only reduced NTD rates by 28-35% (Williams et al., 2015). As such, it is imperative that further work is performed to understand the risk factors associated with NTDs and their underlying mechanisms so that alternative prevention strategies can be developed. However, this is complicated by the sheer number of genes associated with neural tube development, the heterogeneity of observable phenotypes in human cases, the rareness of the disease, and the myriad of environmental factors associated with NTD risk. Given the complex genetic architecture underlying NTD pathology and the way in which that architecture interacts dynamically with environmental factors, further prevention initiatives will undoubtedly require precision medicine strategies that utilize the power of human genomics and modern tools for assessing genetic risk factors. Herein, we review recent advances in genomic strategies for discovering genetic variants associated with these defects, and new ways in which biological models, such as mice and cell culture-derived organoids, are leveraged to assess mechanistic functionality, the way these variants interact with other genetic or environmental factors, and their ultimate contribution to human NTD risk.

The cancer care observation: an empathy training experience.

OBJECTIVE: A 'cancer care observation' (CCO) empathy training is described. This study examined psychiatry trainees' experience of CCO and cancer patients' experience of being observed. METHOD: Trainees were paired with consenting patients undergoing cancer treatment; they observed a number of cancer treatment sessions and chronicled their experiences. The observations were discussed in supervision. Semi-structured interviews were conducted with trainees and observed patients. Observation journals and transcribed interviews were analysed using qualitative description. RESULTS: Seven trainees participated. Three themes emerged: patients used trainees to support themselves while trainees struggled with role identities; CCO extends trainees' professional awareness and can benefit patients; and staff reactions were mixed. Trainees developed wide-ranging, empathic insights into cancer and hospital care experiences. No patient regarded CCO as intrusive. CONCLUSIONS: Trainees garnered insights from CCO as they generated clinical hypotheses, learnt about professional boundaries and gained first-hand experience of unconscious mental processes based on their empathic connections. CCO lends itself to psychiatry and, potentially, other medical trainees.

The role of dental hygienists and therapists in paediatric oral healthcare in Scotland.

Introduction The scope of practice of qualified dental hygienists and therapists allows them to undertake non-surgical periodontal screening, treatment and preventive care, and to diagnose and treatment plan. Therapists are also qualified to restore primary and secondary teeth, and to extract primary teeth. Both professions may see patients directly without needing a dentist's referral. In Scotland, they operate in a context of relatively poor but improving child oral health.Aim To investigate provision of dental care to children, including challenges encountered, by dental hygienists and therapists in the Scottish General Dental Service (GDS).Method An online survey of Scotland-based, GDC-registered dental hygienists and therapists in the GDS.Results Of 426 potential respondents, 194 (46%) responded, including 113 hygienists. Thirty hygienists and six therapists did not currently see child patients. Lack of referrals from dentists/specialisation by other team members, financial/contract reasons and lack of demand were the reasons given. Of those who did see children, most were therapists. Responsibility for preventive paediatric care was evenly split, with 71 (46%) citing the hygienist or therapist and 69 (45%) the dentist. Sixty-five (43%) reported barriers, most commonly relating to parents and children themselves. Time pressures, cost implications for practice and parents, and a number of practice and regulatory barriers were also mentioned.Discussion The response rate is considered to be very good. Limiting factors regarding provision of paediatric dental care include lack of referrals from GDPs and financial or contractual issues.Conclusion There appears to be considerable underuse of hygienists and therapists in respect to paediatric dental care.

The delivery of dental care to older adults in Scotland: a survey of dental hygienists and therapists.

Objectives To explore the level and nature of dental care provided by dental hygienists and therapists to older adults (65 and over) and to identify barriers to such care.Methods An online survey of all GDC-registered hygienists and therapists in Scotland.Results Thirty-two percent (196 of 609) responded. Seventy-five percent worked in general dental practice. Nearly two-thirds of the workload of those in general dental practice was with older patients. Most reported that numbers of such patients were increasing. Fifty-seven percent worked to inflexible appointment slots of 15 or 30 minutes. Time pressure, consent to treatment and power of attorney were the worst administrative problems in the workplace.Only one in four, mainly Public Dental Service (PDS) employees, provided domiciliary care or treated patients in care homes. Common problems in these settings were: poor hygiene, communicating with patients, capacity to consent, power of attorney, insufficient training and time, poor staff liaison, lack of support staff, space and equipment, poor denture storage/maintenance, co-morbidity and NHS charges exemption.Hygienist-therapists, who have a much wider clinical remit than hygienists, often felt their work with older people did not fully utilise their training. There was considerable demand for further training related to the care of older people, with dementia-related training being the most often specified. There was also support for greater professional autonomy through working on a direct access basis and having an NHS list number.Conclusion Respondents working in general practice saw a large proportion of older patients in the practice, while domiciliary and care home visits were largely undertaken by PDS workers. Findings support the conclusion that hygienist-therapists in particular, given their increasing numbers in the UK dental workforce, may be currently under-used in meeting the demand for prevention and treatment of older patients. The combination of demographic and clinical pressure may be met more effectively and economically by developing such 'mid-level' clinical roles in new models of dental care.

Experience of Music Used With Psychedelic Therapy: A Rapid Review and Implications.

Bonny Method of Guided Imagery and Music emerged following discontinuation of psychedelic therapy research in the early 1970s, but psychedelic therapy research has since revived. Music remains a vital component. This study examined participants' experiences of music in psychedelic therapy research. A rapid review of qualitative and quantitative journal articles in four major databases was conducted in February to April, 2019, using the terms hallucinogens, psychedelic, "lysergic acid diethylamide," psilocybin, ayahuasca, music, and/or "music therapy." Of 406 articles retrieved, 10 were included (n = 180; 18-69 years old). Participants had varied backgrounds. Music was widely considered integral for meaningful emotional and imagery experiences and self-exploration during psychedelic therapy. Music transformed through its elicitation of anthropomorphic, transportive, synesthetic, and material sensations. Music could convey love, carry listeners to other realms, be something to "hold," inspire, and elicit a deep sense of embodied transformation. Therapeutic influence was especially evident in music's dichotomous elicitations: Music could simultaneously anchor and propel. Participant openness to music and provision of participant-centered music were associated with optimal immediate and longer-term outcomes. Many studies reported scarce details about the music used and incidental findings of music experienced. Further understanding of participants' idiosyncratic and shared responses to music during drug therapy phases will inform optimal development of flexible music protocols which enhance psychedelic therapy. Music therapists could be involved in the psychedelic therapy research renaissance through assisting with research to optimize music-based protocols used. If psychedelics become approved medicines, music therapists may be involved in offering psychedelic therapy as part of therapeutic teams.

Loss of RAD9B impairs early neural development and contributes to the risk for human spina bifida.

DNA damage response (DDR) genes orchestrating the network of DNA repair, cell cycle control, are essential for the rapid proliferation of neural progenitor cells. To date, the potential association between specific DDR genes and the risk of human neural tube defects (NTDs) has not been investigated. Using whole-genome sequencing and targeted sequencing, we identified significant enrichment of rare deleterious RAD9B variants in spina bifida cases compared to controls (8/409 vs. 0/298; p = .0241). Among the eight identified variants, the two frameshift mutants and p.Gln146Glu affected RAD9B nuclear localization. The two frameshift mutants also decreased the protein level of RAD9B. p.Ser354Gly, as well as the two frameshifts, affected the cell proliferation rate. Finally, p.Ser354Gly, p.Ser10Gly, p.Ile112Met, p.Gln146Glu, and the two frameshift variants showed a decreased ability for activating JNK phosphorylation. RAD9B knockdowns in human embryonic stem cells profoundly affected early differentiation through impairing PAX6 and OCT4 expression. RAD9B deficiency impeded in vitro formation of neural organoids, a 3D cell culture model for human neural development. Furthermore, the RNA-seq data revealed that loss of RAD9B dysregulates cell adhesion genes during organoid formation. These results represent the first demonstration of a DDR gene as an NTD risk factor in humans.

Psilocybin-assisted therapy for depression: How do we advance the field?

In the quest for new treatment options for depression, attention is being paid to the potential role of psychedelic drugs. Psilocybin is of particular interest given its mechanism of action, its benefits in early trials and its relatively low side effects burden. This viewpoint outlines a number of key issues that remain to be elucidated about its potential use in the clinical environment, including clarification of the profile of people most likely to benefit and those who might experience adverse effects, longer-term outcomes and the role of psychotherapeutic input alongside the drug itself. There are also opportunities to understand better, the neurobiology underpinning its effects.

Characteristics of patients with cancer who die by suicide: Coronial case series in an Australian state.

OBJECTIVE: Suicide rates are elevated in epidemiological studies, but extrapolating population level data to the individual patient cancer is difficult, and there is a dearth of studies examining how suicidality might be linked to the cancer experience. We examine the cancer-suicide correlates to explore clinical implications and future research directions. METHOD: We used a novel database to examine all suicide deaths reported to the Coroners Court of Victoria between 2009 and 2013 in individuals with active, diagnosed cancer. Cases were classified in relation to whether cancer had been a probable, possible, or unlikely influence on suicidal ideation. Sociodemographic, clinical, health service contacts, and suicide method data were analysed to describe the characteristics of individuals with cancer at the time of their suicide. RESULTS: There were 2870 suicide deaths, and 118 cases met inclusion criteria. Clinically distinct patient subgroups emerged through a contrast between those cases where the data suggested a correlate between cancer and suicide, and those where the data did not. The former group had many more cancer-related health problems than the latter group, who had a higher burden of psychiatric illness that predated their cancer diagnosis. The intent to suicide was known to most clinicians. CONCLUSIONS: All clinicians working with cancer patients should be prepared to explore suicidal ideation. Understanding how the patient conceptualises suicidality with respect to cancer experience and mental health may be of central importance in determining whether mental health care is best provided as part of cancer care, or through a separate mental health service.

Psychiatric sequelae of corticosteroid use in hematology in Australia: A qualitative study.

Despite widespread steroid usage for treating hematological conditions, minimal attention focuses on associated psychiatric side-effects. In the present study, we examined hematology patients' experiences of high-dose steroid treatment. This was undertaken by the use of a qualitative, descriptive design, which included convenience sampling and the inductive, cyclic, and constant comparative thematic analysis of interview transcripts. Eighteen patients participated, who were diagnosed with lymphoma, myeloma, leukemia, or idiopathic thrombocytopenia purpura. Four themes emerged: side-effects, misattribution of cause, self-management, and fragmented information. The study results revealed that hematology patients administered steroids can experience negligible to extensive erratic side-effects, with severe adverse repercussions. Psychological reactions to steroids are often misattributed. Patients mostly self-manage adverse effects experienced and receive only fragmented preparatory information, often not understanding steroid side-effects. Nurses could provide helpful "in the moment" education for inpatients who misunderstood steroid-related adverse effects, such as aggressive urges. Adverse repercussions for family were occasionally evident. Education, support, and ongoing care for patients experiencing adverse steroid side-effects are inadequate. Health professionals need to develop patient- and family-centered educational resources for potential, unpredictable, and usually adverse steroid side-effects.

Alternative metrics for real-ear-to-coupler difference average values in children.

BACKGROUND: Ideally, individual real-ear-to-coupler difference (RECD) measurements are obtained for pediatric hearing instrument-fitting purposes. When RECD measurements cannot be obtained, age-related average RECDs based on typically developing North American children are used. Evidence suggests that these values may not be appropriate for populations of children with retarded growth patterns. PURPOSE: The purpose of this study was to determine if another metric, such as head circumference, height, or weight, can be used for prediction of RECDs in children. RESEARCH DESIGN: Design was a correlational study. For all participants, RECD values in both ears, head circumference, height, and weight were measured. STUDY SAMPLE: The sample consisted of 68 North American children (ages 3-11 yr). DATA COLLECTION AND ANALYSIS: Height, weight, head circumference, and RECDs were measured and were analyzed for both ears at 500, 750, 1000, 1500, 2000, 3000, 4000, and 6000 Hz. A backward elimination multiple-regression analysis was used to determine if age, height, weight, and/or head circumference are significant predictors of RECDs. RESULTS: For the left ear, head circumference was retained as the only statistically significant variable in the final model. For the right ear, head circumference was retained as the only statistically significant independent variable at all frequencies except at 2000 and 4000 Hz. At these latter frequencies, weight was retained as the only statistically significant independent variable after all other variables were eliminated. CONCLUSIONS: Head circumference can be considered as a metric for RECD prediction in children when individual measurements cannot be obtained. In developing countries where equipment is often unavailable and stunted growth can reduce the value of using age as a metric, head circumference can be considered as an alternative metric in the prediction of RECDs.

Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition.

GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2(-/-)) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2(-/-) mice show cortical PV(+) interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus. Ccnd2(-/-) mice show several neurophysiological and behavioral phenotypes that would be predicted to be produced by hippocampal disinhibition, including increased ventral tegmental area dopamine neuron population activity, behavioral hyperresponsiveness to amphetamine, and impairments in hippocampus-dependent cognition. Remarkably, transplantation of cells from the embryonic medial ganglionic eminence (the major origin of cerebral cortical interneurons) into the adult Ccnd2(-/-) caudoventral hippocampus reverses these psychosis-relevant phenotypes. Surviving neurons from these transplants are 97% GABAergic and widely distributed within the hippocampus. Up to 6 mo after the transplants, in vivo hippocampal metabolic activity is lowered, context-dependent learning and memory is improved, and dopamine neuron activity and the behavioral response to amphetamine are normalized. These findings establish functional links between hippocampal GABA interneuron deficits and psychosis-relevant dopaminergic and cognitive phenotypes, and support a rationale for targeting limbic cortical interneuron function in the prevention and treatment of schizophrenia.

Pilot implementation of computerized cognitive behavioral therapy in a university health setting.

This study evaluated the implementation of computerized cognitive-behavioral therapy (cCBT) for depression and anxiety in a university health center. Students reporting symptoms of depression and/or anxiety were offered cCBT and randomized to a session email reminder or no-reminder condition. Participants reported significant symptom and functional improvement after receiving treatment, comparable to outcomes achieved in controlled efficacy trials. However, rates of session completion were low, and reminders did not enhance retention. Results suggest that cCBT is a promising intervention in this population, with little attenuation of gains relative to efficacy trials but low levels of treatment completion.

IQuaD dental trial; improving the quality of dentistry: a multicentre randomised controlled trial comparing oral hygiene advice and periodontal instrumentation for the prevention and management of periodontal disease in dentate adults attending dental primary care.

BACKGROUND: Periodontal disease is the most common oral disease affecting adults, and although it is largely preventable it remains the major cause of poor oral health worldwide. Accumulation of microbial dental plaque is the primary aetiological factor for both periodontal disease and caries. Effective self-care (tooth brushing and interdental aids) for plaque control and removal of risk factors such as calculus, which can only be removed by periodontal instrumentation (PI), are considered necessary to prevent and treat periodontal disease thereby maintaining periodontal health. Despite evidence of an association between sustained, good oral hygiene and a low incidence of periodontal disease and caries in adults there is a lack of strong and reliable evidence to inform clinicians of the relative effectiveness (if any) of different types of Oral Hygiene Advice (OHA). The evidence to inform clinicians of the effectiveness and optimal frequency of PI is also mixed. There is therefore an urgent need to assess the relative effectiveness of OHA and PI in a robust, sufficiently powered randomised controlled trial (RCT) in primary dental care. METHODS/DESIGN: This is a 5 year multi-centre, randomised, open trial with blinded outcome evaluation based in dental primary care in Scotland and the North East of England. Practitioners will recruit 1860 adult patients, with periodontal health, gingivitis or moderate periodontitis (Basic Periodontal Examination Score 0-3). Dental practices will be cluster randomised to provide routine OHA or Personalised OHA. To test the effects of PI each individual patient participant will be randomised to one of three groups: no PI, 6 monthly PI (current practice), or 12 monthly PI.Baseline measures and outcome data (during a three year follow-up) will be assessed through clinical examination, patient questionnaires and NHS databases.The primary outcome measures at 3 year follow up are gingival inflammation/bleeding on probing at the gingival margin; oral hygiene self-efficacy and net benefits. DISCUSSION: IQuaD will provide evidence for the most clinically-effective and cost-effective approach to managing periodontal disease in dentate adults in Primary Care. This will support general dental practitioners and patients in treatment decision making. TRIAL REGISTRATION: Protocol ID: ISRCTN56465715.

Lipoprotein receptor-related protein-6 protects the brain from ischemic injury.

BACKGROUND AND PURPOSE: Loss-of-function mutations of the lipoprotein receptor-related protein-6 (LRP6), a coreceptor in the Wingless-related integration site-ß-catenin prosurvival pathway, have been implicated in myocardial ischemia and neurodegeneration. However, it remains to be established whether LRP6 is also involved in ischemic brain injury. We used LRP6+/- mice to examine the role of this receptor in the mechanisms of focal cerebral ischemia. METHODS: Focal cerebral ischemia was induced by transient occlusion of the middle cerebral artery. Motor deficits and infarct volume were assessed 3 days later. Glycogen-synthase-kinase-3ß (GSK-3ß) phosphorylation was examined by Western blotting with phosphospecific antibodies, and the mitochondrial membrane potential changes induced by Ca2+ were also assessed. RESULTS: LRP6+/- mice have larger stroke and more severe motor deficits, effects that were independent of intraischemic cerebral blood flow, vascular factors, or cytosolic ß-catenin levels. Rather, LRP6 haploinsufficiency increased the activating phosphorylation and decreased the inhibitory phosphorylation of GSK-3ß, a kinase involved in proinflammatory signaling and mitochondrial dysfunction. Accordingly, postischemic inflammatory gene expression was enhanced in LRP6+/- mice. Furthermore, the association of mitochondria with activated GSK-3ß was increased in LRP6+/- mice, resulting in a reduction in the Ca2+ handling ability of mitochondria. The mitochondrial dysfunction was reversed by pharmacological inhibition of GSK-3ß. CONCLUSIONS: LRP6 activates an endogenous neuroprotective pathway that acts independently of ß-catenin by controlling GSK-3ß activity and preventing its deleterious mitochondrial and proinflammatory effects. The findings raise the possibility that emerging treatment strategies for diseases attributable to LRP6 loss-of-function mutations could also lead to new therapeutic avenues for ischemic stroke.

Lis1 controls dynamics of neuronal filopodia and spines to impact synaptogenesis and social behaviour.

LIS1 (PAFAH1B1) mutation can impair neuronal migration, causing lissencephaly in humans. LIS1 loss is associated with dynein protein motor dysfunction, and disrupts the actin cytoskeleton through disregulated RhoGTPases. Recently, LIS1 was implicated as an important protein-network interaction node with high-risk autism spectrum disorder genes expressed in the synapse. How LIS1 might participate in this disorder has not been investigated. We examined the role of LIS1 in synaptogenesis of post-migrational neurons and social behaviour in mice. Two-photon imaging of actin-rich dendritic filopodia and spines in vivo showed significant reductions in elimination and turnover rates of dendritic protrusions of layer V pyramidal neurons in adolescent Lis1(+/-) mice. Lis1(+/-) filopodia on immature hippocampal neurons in vitro exhibited reduced density, length and RhoA dependent impaired dynamics compared to Lis1(+/+) . Moreover, Lis1(+/-) adolescent mice exhibited deficits in social interaction. Lis1 inactivation restricted to the postnatal hippocampus resulted in similar deficits in dendritic protrusion density and social interactions. Thus, LIS1 plays prominently in dendritic filopodia dynamics and spine turnover implicating reduced dendritic spine plasticity as contributing to developmental autistic-like behaviour.

Factors that distinguish college students with depressive symptoms with and without suicidal thoughts.

BACKGROUND: Suicide among college students is a significant public health concern. Although suicidality is linked to depression, not all depressed college students experience suicidal ideation (SI). The primary aim of this study was to determine potential factors that may distinguish college students with depressive symptoms with and without SI. METHODS: A total of 287 undergraduate college students with substantial depressive symptoms (Beck Depression Inventory [BDI] total score >13) with and without SI were compared across psychiatric and functional outcome variables. Independent sample t tests were conducted for each outcome variable using the suicide item of the BDI as a dichotomous (ie, zero vs nonzero score) grouping variable. RESULTS: Relative to students with substantial depressive symptoms without SI, those with SI were more symptomatic overall, having significantly higher levels of depressive symptoms, hopelessness, and anxiety. However, contrary to our expectations, nonsuicidal and suicidal students did not differ on measures of everyday functioning (ie, cognitive and physical functioning and grade point average). CONCLUSIONS: Our findings suggest that SI among college students is associated with increased subjective distress but may not adversely impact physical or cognitive functioning or academic performance.