Blunted Glucocorticoid Responsiveness to Stress Causes Behavioral and Biological Alterations That Lead to Posttraumatic Stress Disorder Vulnerability.

BACKGROUND: Understanding why only a subset of trauma-exposed individuals develop posttraumatic stress disorder is critical for advancing clinical strategies. A few behavioral (deficits in fear extinction) and biological (blunted glucocorticoid levels, small hippocampal size, and rapid-eye-movement sleep [REMS] disturbances) traits have been identified as potential vulnerability factors. However, whether and to what extent these traits are interrelated and whether one of them could causally engender the others are not known. METHODS: In a genetically selected rat model of reduced corticosterone responsiveness to stress, we explored posttraumatic stress disorder-related biobehavioral traits using ex vivo magnetic resonance imaging, cued fear conditioning, and polysomnographic recordings combined with in vivo photometric measurements. RESULTS: We showed that genetic selection for blunted glucocorticoid responsiveness led to a correlated multitrait response, including impaired fear extinction (observed in males but not in females), small hippocampal volume, and REMS disturbances, supporting their interrelatedness. Fear extinction deficits and concomitant disruptions in REMS could be normalized through postextinction corticosterone administration, causally implicating glucocorticoid deficiency in two core posttraumatic stress disorder-related risk factors and manifestations. Furthermore, reduced REMS was accompanied by higher norepinephrine levels in the hippocampal dentate gyrus that were also reversed by postextinction corticosterone treatment. CONCLUSIONS: Our results indicate a predominant role for glucocorticoid deficiency over the contribution of reduced hippocampal volume in engendering both REMS alterations and associated deficits in fear extinction consolidation, and they causally implicate blunted glucocorticoids in sustaining neurophysiological disturbances that lead to fear extinction deficits.

Ultrasound-guided hepatic portal vein injection is not a reproducible technique for delivery of cell therapies to the liver in mice.

AIMS: Our aim was to determine if ultrasound-guided HPV injection in mice would provide reproducible and reliable results, as is currently obtained via open laparotomy techniques, and offer a surgical refinement to emulate islet transplantation in humans. METHODS: Fluorescent-polymer microparticles (20 µm) were injected (27G-needle) into the HPV via open laparotomy (n = 4) or under ultrasound-guidance (n = 4) using an MX550D-transducer with a Vevo3100-scanner (FUJIFILM VisualSonics, Inc.). Mice were culled 24-h post injection; organs were frozen, step sectioned (10 µm-slices) and 10 sections/mouse (50 µm-spacing) were quantified for microparticles in the liver and other organs by fluorescent microscopy. RESULTS: Murine HPV injection, via open laparotomy-route, resulted in widespread distribution of microparticles in the liver, lungs and spleen; ultrasound-guided injection resulted in reduced microparticle delivery (p < 0.0001) and microparticle clustering in distinct areas of the liver at the site of needle penetration, with very few/no microparticles being seen in lung and spleen tissues, hypothesised to be due to flow into the body cavity: liver median (interquartile range) 4.15 (0.00-4.15) versus 0.00 (0.00-0.00) particle-count mm-2 , respectively. CONCLUSIONS: Ultrasound-guided injection results in microparticle clustering in the liver, with an overall reduction in microparticle number when compared to open laparotomy HPV injection, and high variability in microparticle-counts detected between mice. Ultrasound-guided injection is not currently a technique that can replace open laparotomy HPV of islet transplantation in mice.

Sex-specific differences in cardiac function, inflammation and injury during early polymicrobial sepsis.

BACKGROUND: Sex differences in sepsis are underexplored and incompletely understood. Cardiac function in early sepsis is pivotal in determining survival; hyperdynamic left ventricular ejection fraction is associated with higher mortality. Female sex may be cardioprotective, but variable experimental findings have not controlled for hypovolaemia. Sex-specific local cardiac versus peripheral inflammation in causing cardiovascular dysfunction also remain unclear. We therefore examined whether there are sex-specific differences in cardiac function in early sepsis, controlling for volaemic status and sex-specific differences in the peripheral inflammatory response initiated by tumour necrosis factor (TNFα). METHODS: We used an experimental polymicrobial sepsis (faecal slurry) model titrated to minimise hypovolaemia as a confounding factor. We quantified cardiac function (transthoracic cardiac echocardiography) 1 week before, and 18 h after, sepsis. Cardiac injury (troponin I), inflammation and immune cell infiltration (flow cytometry) were quantified in naïve and septic female and male mice 18 h after sepsis. To evaluate the sex-specific influence of TNFα derived from peripheral leukocytes, we repeated the experiments in iRHOM2-/- mice that are unable to shed TNFα exclusively from circulating leucocytes. RESULTS: Serum troponin I increased to 1.39 ± 0.38 ng mL-1 (from undetectable levels in controls) 18 h after onset of normovolaemic sepsis to a similar extent in both sexes. Stroke volume in male mice increased by 8 µL [(3-13); p = 0.004], compared to individualised pre-sepsis values. By contrast, stroke volume remained at baseline levels in females [mean difference: 4 µL (- 1 to 9)]. Messenger RNA levels of markers for cardiac injury/inflammation after sepsis (real-time polymerase-chain reaction) were elevated in male wild-type mice compared to female wild types (n = 10/sex), with higher cardiac mRNA levels of atrial natriuretic peptide, inflammation (TNFα) and oxidative stress (superoxide dismutase-1), although serum troponin I values were similarly elevated. Flow cytometry analysis of cardiac tissue showed doubling of CD4 + leukocyte infiltration in male mice. Sex-specific cardiac physiologic differences were similar in iRHOM2-/- mice that are unable to shed TNFα exclusively from leucocytes. CONCLUSIONS: In early normovolaemic polymicrobial sepsis, a relative hyperdynamic response develops in male mice. Myocardial stress/injury after early sepsis is limited in females, with less cardiac infiltration of CD4 + leukocytes but independent of shedding of TNFα from peripheral circulating leukocytes.

Hooked on heart regeneration: the zebrafish guide to recovery.

While humans lack sufficient capacity to undergo cardiac regeneration following injury, zebrafish can fully recover from a range of cardiac insults. Over the past two decades, our understanding of the complexities of both the independent and co-ordinated injury responses by multiple cardiac tissues during zebrafish heart regeneration has increased exponentially. Although cardiomyocyte regeneration forms the cornerstone of the reparative process in the injured zebrafish heart, recent studies have shown that this is dependent on prior neovascularization and lymphangiogenesis, which in turn require epicardial, endocardial, and inflammatory cell signalling within an extracellular milieu that is optimized for regeneration. Indeed, it is the amalgamation of multiple regenerative systems and gene regulatory patterns that drives the much-heralded success of the adult zebrafish response to cardiac injury. Increasing evidence supports the emerging paradigm that developmental transcriptional programmes are re-activated during adult tissue regeneration, including in the heart, and the zebrafish represents an optimal model organism to explore this concept. In this review, we summarize recent advances from the zebrafish cardiovascular research community with novel insight into the mechanisms associated with endogenous cardiovascular repair and regeneration, which may be of benefit to inform future strategies for patients with cardiovascular disease.

Considerations and challenges of islet transplantation and future therapies on the horizon.

Islet transplantation is a treatment for selected adults with type 1 diabetes and severe hypoglycemia. Islets from two or more donor pancreases, a scarce resource, are usually required to impact glycemic control, but the treatment falls short of a cure. Islets are avascular when transplanted into the hypoxic liver environment and subjected to inflammatory insults, immune attack, and toxicity from systemic immunosuppression. The Collaborative Islet Transplant Registry, with outcome data on over 1,000 islet transplant recipients, has demonstrated that larger islet numbers transplanted and older age of recipients are associated with better outcomes. Induction with T-cell depleting agents and the TNF-α inhibitor etanercept and maintenance systemic immunosuppression with mTOR inhibitors in combination with calcineurin inhibitors also appear advantageous, but concerns remain over immunosuppressive toxicity. We discuss strategies and therapeutics that address specific challenges of islet transplantation, many of which are at the preclinical stage of development. On the horizon are adjuvant cell therapies with mesenchymal stromal cells and regulatory T cells that have been used in preclinical models and in humans in other contexts; such a strategy may enable reductions in immunosuppression in the early peri-transplant period when the islets are vulnerable to apoptosis. Human embryonic stem cell-derived islets are in early-phase clinical trials and hold the promise of an inexhaustible supply of insulin-producing cells; effective encapsulation of such cells or, silencing of the human leukocyte antigen (HLA) complex would eliminate the need for immunosuppression, enabling this therapy to be used in all those with type 1 diabetes.

Ethical Issues in Consent for the Reuse of Data in Health Data Platforms.

Data platforms represent a new paradigm for carrying out health research. In the platform model, datasets are pooled for remote access and analysis, so novel insights for developing better stratified and/or personalised medicine approaches can be derived from their integration. If the integration of diverse datasets enables development of more accurate risk indicators, prognostic factors, or better treatments and interventions, this obviates the need for the sharing and reuse of data; and a platform-based approach is an appropriate model for facilitating this. Platform-based approaches thus require new thinking about consent. Here we defend an approach to meeting this challenge within the data platform model, grounded in: the notion of 'reasonable expectations' for the reuse of data; Waldron's account of 'integrity' as a heuristic for managing disagreement about the ethical permissibility of the approach; and the element of the social contract that emphasises the importance of public engagement in embedding new norms of research consistent with changing technological realities. While a social contract approach may sound appealing, however, it is incoherent in the context at hand. We defend a way forward guided by that part of the social contract which requires public approval for the proposal and argue that we have moral reasons to endorse a wider presumption of data reuse. However, we show that the relationship in question is not recognisably contractual and that the social contract approach is therefore misleading in this context. We conclude stating four requirements on which the legitimacy of our proposal rests.

Informing National Health Service patients about participation in clinical research: A comparison of opt-in and opt-out approaches across the United Kingdom.

OBJECTIVE: Recruitment to clinical research in the National Health Service remains challenging. One barrier is accessing patients to discuss research participation. Two general approaches are used in the United Kingdom to facilitate this: an 'opt-in' approach (when clinicians communicate research opportunities to patients) and an 'opt-out' approach (all patients have the right to be informed of relevant research opportunities). No evidence-based data are available, however, to inform the decision about which approach is preferable. This study aimed to collect information from 'opt-in' and 'opt-out' Trusts and identify which of the two approaches is optimal for ensuring National Health Service patients are given opportunities to discuss research participation. METHOD: This sequential mixed methods study comprised three phases: (1) an Appreciative Inquiry across UK Trusts, (2) online surveys and (3) focus groups with National Health Service staff and patients at a representative mental health Trust. RESULTS: The study was conducted between June and October 2019. Out of seven National Health Service Mental Health Trusts contacted (three 'opt-out' and four 'opt-in'), only four took part in phase 1 of the study and three of them were 'opt-out' Trusts. Benefits of an 'opt-out' approach included greater inclusivity of patients and the removal of research gatekeepers, while the involvement of research-active clinicians and established patient-clinician relationships were cited as important to 'opt-in' success. Phases 2 and 3 were conducted at a different Trust (Oxford Health NHS Foundation Trust) which was using an 'opt-in' approach. Of 333 staff and member survey responders, 267 (80.2%) favoured moving to an 'opt-out' approach (phase 2). Nineteen staff and 16 patients and carers participated in focus groups (phase 3). Concern was raised by staff regarding the lack of time for clinical research, with clinical work taking precedence over research; patients were concerned about a lack of research activity; all considered research to be beneficial and were supportive of a move to 'opt-out'. CONCLUSION: Findings suggest that 'opt-out' is more beneficial than 'opt-in', with the potential to vastly increase patient access to research opportunities and to enable greater equality of information provision for currently marginalised groups. This should ensure that healthcare research is more representative of the entire population, including those with a mental health diagnosis.

Mental health of forced migrants recently granted leave to remain in the United Kingdom.

BACKGROUND: Asylum seekers who are granted leave to remain in the United Kingdom are required to make a rapid transition to housing and welfare benefits. The challenges facing new refugees during this 'transition period' can affect their mental health, but this has not been quantified. AIMS: To assess the impact of the transition period on new refugees' mental health in the 12 months after being granted leave to remain in the United Kingdom. METHOD: A longitudinal survey design was used to measure the mental health of 30 newly recognised refugees at monthly intervals in the first 6 months and again at 1 year after receiving leave to remain in the United Kingdom. There were five outcome measures for symptoms of anxiety, depression, distress, post-traumatic stress disorder (PTSD), post-migration living difficulties (PMLD) and a life events calendar to record key changes in housing and welfare. RESULTS: The results showed that the trajectory of scores across all measures fluctuates, but overall they all improve from baseline to Month 12. Scores for depression and PMLD showed significant improvement at Month 5, and scores for anxiety, depression, distress and PMLD showed significant improvement at Month 12. PTSD scores did not show significant improvement at any month. In months with a high number of stressful life events, participants had worse PMLD and PTSD scores. CONCLUSION: Overall improvement in mental health could partly be explained by the stability of being granted leave to remain in the United Kingdom, but may also be due to the high level of practical support these participants received. Recommendations are made for those working with clients during the transition period.

Epidemiology and survival outcomes in stages II and III cutaneous melanoma: a systematic review.

AIM: Management of cutaneous melanoma (CM) is continually evolving with adjuvant treatment of earlier stage disease. The aim of this review was to identify published epidemiological data for stages II-III CM. MATERIALS & METHODS: Systematic searches of Medline and Embase were conducted to identify literature reporting country/region-specific incidence, prevalence, survival or mortality outcomes in stage II and/or III CM. Screening was carried out by two independent reviewers. RESULTS & CONCLUSION: Of 41 publications, 14 described incidence outcomes (incidence rates per stage were only reported for US and Swedish studies), 33 reported survival or mortality outcomes and none reported prevalence data. This review summarizes relevant data from published literature and highlights an overall paucity of epidemiological data in stages II and III CM.

Consent to discuss participation in research: a pilot study.

BACKGROUND: Equitable access to research studies needs to be increased for all patients. There is debate about which is the best approach to use to discuss participation in research in real-world clinical settings. OBJECTIVE: We aimed to determine the feasibility of asking all clinical staff within one hospital Trust (an organisation that provides secondary health services within the English and Welsh National Health Service) to use a newly created form on the Trust's electronic patient records system, as a means of asking patients to consent to discuss participation in research (the opt-in approach). We also aimed to collect feedback from patients and clinicians about their views of the opt-in approach. METHODS: Four pilot sites were selected in the Trust: two memory clinics, an adult mental health team and an acute adult ward. Data were collected in three phases: (1) for 6 months, pilot site staff were asked to complete a consent to discuss participation in research form with patients; (2) staff feedback on the form was collected through an online survey; and (3) patient feedback was collected through focus groups. FINDINGS: Of 1779 patients attending services during the pilot period, 197 (11%) had a form completed by staff and 143 (8%) opted-in to finding out about research. Staff cited limited time, low priority and poor user experience of the electronic patient records system as reasons for low uptake of the form. Patients generally approved of the approach but offered suggestions for improvement. CONCLUSIONS: There were mixed results for adopting an opt-in approach; uptake was very low, limiting its value as an effective strategy for improving access to research. CLINICAL IMPLICATIONS: Alternative strategies to the opt-in approach, such as transparent opt out approaches, warrant consideration to maximise access to research within routine clinical care.

The burden of proof: The process of involving young people in research.

Patient and public involvement in research includes non-academics working with researchers, on activities from consultative tasks, to joint working, and on user-led initiatives. Health and social care funding bodies require involvement in research projects. A current debate focuses on a perceived lack of empirical "proof" to demonstrate the impact of involvement upon the quality of research. It is also argued that the working relationships between researchers and those becoming involved need to be understood more fully. These areas are beginning to be reported upon but there are few studies of young people involved in health research. This study describes the experiences of adult academics and young people, working together on a large-scale, UK health research programme. Using qualitative interview and focus group methods, the aim was to explore participants' perceptions about the process and outcomes of their work together. The importance of cyclical, dynamic and flexible approaches is suggested. Enablers include having clear mechanisms for negotiation and facilitation, stakeholders having a vision of "the art of the possible," and centrally, opportunities for face-to-face working. What is needed is a continuing discourse about the challenges and benefits of working with young people, as distinct from younger children and adults, understanding the value of this work, without young people having to somehow "prove" themselves. Involvement relies on complex social processes. This work supports the view that an improved understanding of how key processes are enabled, as well as what involvement achieves, is now needed.

Early-life stress influences acute and sensitized responses of adult mice to cocaine by interacting with GABAA α2 receptor expression.

Early-life stress (ELS) is known to exert long-term effects on brain function, with resulting deleterious consequences for several aspects of mental health, including the development of addiction to drugs of abuse. One potential mechanism in humans is suggested by findings that ELS interacts with polymorphisms of the GABRA2 gene, encoding α2 subunits of GABAA receptors, to increase the risk for both post-traumatic stress disorder and vulnerability to cocaine addiction. We used a mouse model, in which the amount of material for nest building was reduced during early postnatal life, to study interactions between ELS and expression of α2-containing GABAA receptors in influencing cocaine-related behaviour. Breeding of parents heterozygous for a deletion of α2 resulted in litters containing homozygous knockout (α2), heterozygous knockout (α2) and wild-type (α2) offspring. Following the ELS procedure, the mice were allowed to develop to adulthood before being tested for the acute effect of cocaine on locomotor stimulation, behavioural sensitization to repeated cocaine and to cocaine-conditioned activity. Exposure to ELS resulted in increased acute locomotor stimulant effects of cocaine across all genotypes, with the most marked effects in α2 mice (which also showed increased activity following vehicle). Repeated cocaine administration to nonstressed mice resulted in sensitization in α2 and α2 mice, but, in keeping with previous findings, not in α2 mice. Previous exposure to ELS reduced sensitization in α2 mice, albeit not significantly, and abolished sensitization in α2 mice. Conditioned activity was elevated following ELS in all animals, independently of genotype. Thus, while the enhanced acute effects of cocaine following ELS being most marked in α2 mice suggests a function of α2-containing GABAA receptors in protecting against stress, the interaction between ELS and genotype in influencing sensitization may be more in keeping with ELS reducing expression of α2-containing GABAA receptors. The ability of ELS to increase cocaine-conditioned locomotor activity appears to be independent of α2-containing GABAA receptors.

Alterations in brain microstructure in rats that develop abnormal aggression following peripubertal stress.

Exposure to early adversity is implicated in the development of aggressive behaviour later in life in some but not all individuals. The reasons for the variability in response to such experiences are not clear but may relate to pre-existing individual differences that influence their downstream effects. Applying structural magnetic resonance imaging (MRI) to a rat model of abnormal aggression induced by peripubertal stress, we examined whether individual differences in the development of an aggressive phenotype following stress exposure were underpinned by variation in the structure of aggression-associated, corticolimbic brain regions. We also assessed whether responsiveness of the hypothalamic-pituitary-adrenal axis to stress was associated with neurobehavioural outcome following adversity. A subset of the rats exposed to peripubertal stress developed an aggressive phenotype, while the remaining rats were affected in other behavioural domains, such as increased anxiety-like behaviours and reduced sociability. Peripubertal stress led to changes in tissue microstructure within prefrontal cortex, amygdala and hippocampal formation only in those individuals displaying an aggressive phenotype. Attenuated glucocorticoid response to stress during juvenility predicted the subsequent development of an aggressive phenotype in peripubertal stress-exposed rats. Our study establishes a link between peripubertal stress exposure in rats and structural deviations in brain regions linked to abnormal aggression and points towards low glucocorticoid responsiveness to stress as a potential underlying mechanism. We additionally highlight the importance of considering individual differences in behavioural response to stress when determining neurobiological correlates.

Perioperative management of angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers: a survey of perioperative medicine practitioners.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are the most commonly prescribed antihypertensive medications in higher-risk surgical patients. However, there is no clinical consensus on their use in the perioperative period, in part, due to an inconsistent evidence-base. To help inform the design of a large multi-centre randomized controlled trial (ISRCTN17251494), we undertook a questionnaire-based survey exploring variability in ACEi/ARB prescribing in perioperative practice. METHODS: The online survey included perioperative scenarios to examine how consistent respondents were with their stated routine preoperative practice. Clinicians with an academic interest in perioperative medicine were primarily targeted between July and September 2017. STROBE guidelines for observational research and ANZCA Trials Group Survey Reporting recommendations were adhered to. RESULTS: 194 responses were received, primarily from clinicians practicing in the UK. A similar minority of respondents continue ACEi (n = 57; 30%) and ARBs (n = 62; 32%) throughout the perioperative period. However, timing of preoperative cessation was highly variable, and rarely influenced by the pharmacokinetics of individual ACE-i/ARBs. Respondents' stated routine practice was frequently misaligned with their management of common pre- and postoperative scenarios involving continuation or restarting ACE-i/ARBs. DISCUSSION: This survey highlights many inconsistencies amongst clinicians' practice in perioperative ACE-i/ARB management. Studies designed to reveal an enhanced understanding of perioperative mechanisms at play, coupled with randomised controlled trials, are required to rationally inform the clinical management of ACE-i/ARBs in patients most at risk of postoperative morbidity.

Long-term programing of psychopathology-like behaviors in male rats by peripubertal stress depends on individual's glucocorticoid responsiveness to stress.

Experience of adversity early in life and dysregulation of hypothalamus-pituitary-adrenocortical (HPA) axis activity are risk factors often independently associated with the development of psychopathological disorders, including depression, PTSD and pathological aggression. Additional evidence suggests that in combination these factors may interact to shape the development and expression of psychopathology differentially, though little is known about underlying mechanisms. Here, we studied the long-term consequences of early life stress exposure on individuals with differential constitutive glucocorticoid responsiveness to repeated stressor exposure, assessing both socio-affective behaviors and brain activity in regions sensitive to pathological alterations following stress. Two rat lines, genetically selected for either low or high glucocorticoid responsiveness to repeated stress were exposed to a series of unpredictable, fear-inducing stressors on intermittent days during the peripuberty period. Results obtained at adulthood indicated that having high glucocorticoid responses to repeated stress and having experience of peripuberty stress independently enhanced levels of psychopathology-like behaviors, as well as increasing basal activity in several prefrontal and limbic brain regions in a manner associated with enhanced behavioral inhibition. Interestingly, peripuberty stress had a differential impact on aggression in the two rat lines, enhancing aggression in the low-responsive line but not in the already high-aggressive, high-responsive rats. Taken together, these findings indicate that aberrant HPA axis activity around puberty, a key period in the development of social repertoire in both rats and humans, may alter behavior such that it becomes anti-social in nature.

The link between aberrant hypothalamic-pituitary-adrenal axis activity during development and the emergence of aggression-Animal studies.

Aggressive behavior is not uniform, including proactive and reactive forms of aggression. Aberrant functioning of the hypothalamic-pituitary-adrenal (HPA) axis is frequently associated with abnormal aggression. Here, we review the rodent literature in order to assess whether developmental abnormalities in the HPA axis can be causally linked with the emergence of abnormal aggression. We examine studies that involve genetic models and life challenges (e.g., early life stress, drug exposure) that course with developmental alterations in the HPA axis. Although the lack of systematic studies hinders development of an integrated model, existing evidence supports a U-shaped function regarding differences in HPA axis functioning during development and the emergence of aggressive phenotypes. Thus, developmentally low or high HPA axis reactivity are typically found to be aligned with the emergence of aggressive phenotypes; however, existing information is insufficient to causally link divergent HPA axis aberration with specific types of aggression. Progress in this field is needed to support interventions in children aimed at ameliorating social dysfunctions associated with aberrations in HPA axis function.

Constitutive differences in glucocorticoid responsiveness to stress are related to variation in aggression and anxiety-related behaviors.

Glucocorticoids coordinate responses that enable an individual to cope with stressful challenges and, additionally, mediate adaptation following cessation of a stressor. There are important individual differences in the magnitude of glucocorticoid responsiveness to stressors. However, whether individual differences in glucocorticoid responsiveness to stress are linked to different behavioral strategies in coping with social and non-social challenges is not easily studied, owing to the lack of appropriate animal models. To address this, we generated three lines of Wistar rats selectively bred for the magnitude of their glucocorticoid responses following exposure to a variety of stressors over three consecutive days at juvenility. Here, we present findings following observations of a high level of variation in glucocorticoid responsiveness to stress in outbred Wistar rats, and the strong response to selection for this trait over a few generations. When challenged with different stressful challenges, rats from the three lines differed in their coping behaviors. Strikingly, the line with high glucocorticoid responsiveness to stress displayed enhanced aggression and anxiety-like behaviors. In addition, these rats also showed alterations in the expression of genes within both central and peripheral nodes of the hypothalamic-pituitary-adrenal (HPA) axis and enhanced reactivity to acute stress exposure. Together, these findings strongly link differences in glucocorticoid responsiveness to stress with marked differences in coping styles. The developed rat lines are thus a promising model with which to examine the relationship between variation in reactivity of the HPA axis and stress-related pathophysiology and could be employed to assess the therapeutic potential of treatments modulating stress habituation to ameliorate psychopathology.

Deficiency of Cks1 Leads to Learning and Long-Term Memory Defects and p27 Dependent Formation of Neuronal Cofilin Aggregates.

In mitotic cells, the cyclin-dependent kinase (CDK) subunit protein CKS1 regulates S phase entry by mediating degradation of the CDK inhibitor p27. Although mature neurons lack mitotic CDKs, we found that CKS1 was actively expressed in post-mitotic neurons of the adult hippocampus. Interestingly, Cks1 knockout (Cks1-/-) mice exhibited poor long-term memory, and diminished maintenance of long-term potentiation in the hippocampal circuits. Furthermore, there was neuronal accumulation of cofilin-actin rods or cofilin aggregates, which are associated with defective dendritic spine maturation and synaptic loss. We further demonstrated that it was the increased p27 level that activated cofilin by suppressing the RhoA kinase-mediated inhibitory phosphorylation of cofilin, resulting in the formation of cofilin aggregates in the Cks1-/- neuronal cells. Consistent with reports that the peptidyl-prolyl-isomerase PIN1 competes with CKS1 for p27 binding, we found that inhibition of PIN1 diminished the formation of cofilin aggregates through decreasing p27 levels, thereby activating RhoA and increasing cofilin phosphorylation. Our results revealed that CKS1 is involved in normal glutamatergic synapse development and dendritic spine maturation in adult hippocampus through modulating p27 stability.

Retrospective Cohort Study to Assess Outcomes, Cost-Effectiveness, and Patient Satisfaction in Primary Vaginal Ovarian Cystectomy versus the Laparoscopic Approach.

STUDY OBJECTIVE: To compare surgical outcomes, cost-effectiveness, and patient satisfaction in women undergoing primary vaginal or laparoscopic ovarian cystectomy for benign ovarian cysts. DESIGN: Retrospective cohort control study (Canadian Task Force classification II-3). SETTING: Gynecologic unit at a university-affiliated hospital. PATIENTS: Fifty patients who underwent primary ovarian cystectomy either through the vaginal route via posterior colpotomy (n = 29) or laparoscopic route (n = 21). INTERVENTIONS: Nonmalignant ovarian cysts were initially determined by transvaginal ultrasonography and serum tumor markers. The index group of women (n = 29) underwent vaginal ovarian cystectomy via a posterior colpotomy incision, whereas the control group (n = 21) comprised women who had laparoscopic ovarian cystectomy using the traditional "grasp and peel" technique. The following outcomes were evaluated: duration of surgery, intraoperative complications, estimated blood loss, length of inpatient stay, and postoperative pain (visual analogue scale). The average cost of both surgical methods was calculated by factoring in theater time, equipment required, and the length of hospital stay. Patients were then surveyed to compare postoperative pain and satisfaction scores as well as the time taken to return to work (in days). MEASUREMENTS AND MAIN RESULTS: The 2 groups had similar mean ages (35.79 vs 36.72 years) and cyst diameter (6.8 vs 6.6 cm) (p > .05 in both cases). Vaginal ovarian cystectomy took a mean of 13.7 minutes longer (91.7 vs 78.0 minutes, p < .001) to perform and resulted in a greater mean estimated blood loss (116.1 vs 95 mL, p < .001). The spillage rate in the index group was 6-fold less compared with control cases (6% ± 2.4% vs 35% ± 4.6, p < .01). Although patients from the index group spent a mean of 2 hours longer as inpatients (10.9 vs 8.9 hours, p < .001), they reported a lower mean visual analogue pain score (2.01/10 vs 3.95/10, p < .05) and higher patient satisfaction scores (8.2/10 vs 6.5/10, p < .001). Mean perioperative cost of women who underwent vaginal ovarian cystectomy was lower (£1690.13 vs 1761.67) and they returned to work quicker compared with the laparoscopic group (13.6 vs 39.2 days, p < .001). CONCLUSION: Vaginal ovarian cystectomies took longer to perform and led to longer inpatient stay. However, these women had less postoperative pain and reported higher satisfaction scores compared with laparoscopic ovarian cystectomy, with a quicker return to work. The vaginal approach is a viable and cost-effective alternative to the laparoscopic approach in carefully selected patients.

Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition.

Alcohol dependence is a common, complex and debilitating disorder with genetic and environmental influences. Here we show that alcohol consumption increases following mutations to the γ-aminobutyric acidA receptor (GABAAR) ß1 subunit gene (Gabrb1). Using N-ethyl-N-nitrosourea mutagenesis on an alcohol-averse background (F1 BALB/cAnN x C3H/HeH), we develop a mouse model exhibiting strong heritable preference for ethanol resulting from a dominant mutation (L285R) in Gabrb1. The mutation causes spontaneous GABA ion channel opening and increases GABA sensitivity of recombinant GABAARs, coupled to increased tonic currents in the nucleus accumbens, a region long-associated with alcohol reward. Mutant mice work harder to obtain ethanol, and are more sensitive to alcohol intoxication. Another spontaneous mutation (P228H) in Gabrb1 also causes high ethanol consumption accompanied by spontaneous GABA ion channel opening and increased accumbal tonic current. Our results provide a new and important link between GABAAR function and increased alcohol consumption that could underlie some forms of alcohol abuse.