International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function.

5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors. SIGNIFICANCE STATEMENT: This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.

REDESIGNING JUVENILE PROBATION TO ALIGN WITH BEHAVIORAL HEALTH AND POSITIVE DEVELOPMENT PRINCIPLEs: A Quasi-Experimental study.

Science advisory boards and policy organizations have called for adolescent brain science to be incorporated into juvenile probation operations. To achieve this, Opportunity-Based Probation (OBP), a probation model that integrates knowledge of adolescent development and behavior change principles, was developed in collaboration with a local juvenile probation department. The current study compares outcomes (recidivism and probation violations) for youth in the OBP condition versus probation as usual. Inverse probability weighting (IPW) and coarsened exact matching (CEM) were used to estimate causal effects of OBP's average treatment effect (ATE). Results indicated clear effects of OBP on reducing criminal legal referrals, but no significant effects were observed for probation violations. Overall, results provide promising recidivism-reduction effects in support of developmentally grounded redesigns of juvenile probation.

Heard, valued, supported? Doctors' wellbeing during transitions triggered by COVID-19.

INTRODUCTION: Supporting doctors' wellbeing is crucial for medical education to help minimise negative long-term impacts on medical workforce retention and ultimately patient care. There is limited study of how doctors' transitions experiences impact wellbeing, particularly socially and culturally. Multiple Multidimensional Transitions (MMT) theory views transitions as dynamic, incorporating multiple contexts and multiple domains. Using MMT as our lens, we report a qualitative analysis of how transitions experienced by doctors during the pandemic impacted on social and cultural aspects of wellbeing. METHODS: Longitudinal narrative inquiry was employed, using interviews and audio-diaries. Data were collected over 6 months in three phases: (i) interviews with doctors from across the career spectrum (n = 98); (ii) longitudinal audio-diaries for 2-4 months (n = 71); (iii) second interviews (n = 83). Data were analysed abductively, narrowing focus to factors important to social and cultural wellbeing. RESULTS: Doctors described experiencing multiple interacting transitions triggered by the pandemic in multiple contexts (workplace, role, homelife and education). Patterns identifiable across the dataset allowed us to explore social and cultural wellbeing crosscutting beyond individual experience. Three critical factors contributed to social and cultural wellbeing both positively and negatively: being heard (e.g., by colleagues asking how they are); being valued (e.g., removal of rest spaces by organisations showing lack of value); and being supported (e.g., through regular briefing by education bodies). CONCLUSIONS: This study is the first to longitudinally explore the multiple-multidimensional transitions experienced by doctors during the COVID-19 pandemic. Our data analysis helped us move beyond existing perceptions around wellbeing and articulate multiple factors that contribute to social and cultural wellbeing. It is vital that medical educators consider the learning from these experiences to help pinpoint what aspects of support might be beneficial to trainee doctors and their trainers. This study forms the basis for developing evidenced-based interventions that ensure doctors are heard, valued and supported.

Ureteroenteric anastomosis in orthotopic neobladder creation: do urinary tract infections impact stricture rate?

PURPOSE: Radical cystectomy (RC) and urinary diversion in the treatment of muscle-invasive bladder cancer is associated with peri-operative complication rates as high as 60%. Ureteroenteric anastomotic stricture (UEAS) is a potential source significant morbidity often requiring secondary interventions. We sought to evaluate our experience with benign UEAS in our open ileal orthotopic neobladder (ON) population. METHODS: After Internal Review Board (IRB) approval, we performed a retrospective review of patients who had RC and ON between 2000 and 2015 at MD Anderson Cancer Center and had at least 6 months of follow-up. Baseline demographics and treatment characteristics, peri-operative and post-operative outcomes, as well as information regarding anastomosis technique and suture types were evaluated. Patients with malignant ureteral obstruction were excluded from the analysis. RESULTS: 418 patients had ON creation and the mean age was 59 years (SD 9.4 years) and 90% were males. The mean follow-up was 57 months (6-183 months). 37 patients (8.9%) developed UEAS in 42 renal units and the mean time to diagnosis was 15.8 months (0.85-90 months). Anastomosis and suture type were not predictive of UEAS (p = 0.594, p = 0.586). Perioperative UTI within 30 days of surgery, and recurrent UTI were predictive of UEAS, HR 2.4 p = 0.03, HR 5.1 p < 0.001, respectively. CONCLUSIONS: UEAS are associated with potentially significant morbidity following ON creation. UEAS may occur early following ON, but may occur as late as 7 years following surgery. Indeed, technical factors and surgeon experience contribute to the rates of UEAS, but perioperative UTI appears to herald future stricture development.

Subanesthetic ketamine with an AMPAkine attenuates motor impulsivity in rats.

The concept of 'impulse control' has its roots in early psychiatry and today has progressed into a well-described, although poorly understood, multidimensional endophenotype underlying many neuropsychiatric disorders (e.g., attention deficit hyperactivity disorder, schizophrenia, substance use disorders). There is mounting evidence suggesting that the cognitive and/or behavioral dimensions underlying impulsivity are driven by dysfunctional glutamate (Glu) neurotransmission via targeted ionotropic Glu receptor (GluR) [e.g., N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)] mechanisms and associated synaptic alterations within key brain nodes. Ketamine, a noncompetitive NMDAR antagonist and FDA-approved for treatment-resistant depression, induces a 'glutamate burst' that drives resculpting of the synaptic milieu, which lasts for several days to a week. Thus, we hypothesized that single and repeated treatment with a subanesthetic ketamine dose would normalize motor impulsivity. Next, we hypothesized that AMPAR positive allosteric modulation, alone or in combination with ketamine, would attenuate impulsivity and provide insight into the mechanisms underlying GluR dysfunction relevant to motor impulsivity. To measure motor impulsivity, outbred male Sprague-Dawley rats were trained on the one-choice serial reaction time task. Rats pretreated with single or repeated (3 days) administration of ketamine (10 mg/kg; i.p.; 24-h pretreatment) or with the AMPAkine HJC0122 (1 or 10 mg/kg; i.p.; 30-min pretreatment) exhibited lower levels of motor impulsivity vs. control. Combination of single or repeated ketamine plus HJC0122 also attenuated motor impulsivity vs. control. We conclude that ligands designed to promote GluR signaling represent an effective pharmacological approach to normalize impulsivity and subsequently, neuropsychiatric disorders marked by aberrant impulse control.

Fentanyl self-administration impacts brain immune responses in male Sprague-Dawley rats.

Opioid use disorder (OUD) affects over two million in the United States and is an increasing public health crisis. The abuse of fentanyl and the emergence of potent fentanyl derivatives increases the risk for the user to succumb to overdose, but also to develop OUD. While intense attention is currently focused on understanding the complexity of behaviors and neural functions that contribute to OUD, much remains to be discovered concerning the interactions of opioid intake with the immune response in the central nervous system (CNS). In the present studies, we tested the hypothesis that short-term abstinence from fentanyl self-administration associates with altered expression of innate immune markers. Male Sprague-Dawley rats were trained to self-administer fentanyl (0.0032 mg/kg/infusion) to stability followed by 24 h of abstinence. Several innate immune markers, as well as opioid receptors (ORs) and intracellular pattern recognition receptors (PRRs), were interrogated within nodes of the neurocircuitry involved in OUD processes, including the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CPu), hippocampus (HIP) and midbrain (MB). In the present study, few immune targets were impacted in the PFC and MB during short-term abstinence from fentanyl (relative to saline) self-administration. However, increased expression of cytokines [e.g., interleukin (IL)1ß, IL5], chemokines [e.g., C-C motif chemokine 20 (MIP3α)], tumor necrosis factor α (TNFα) and interferon (IFN) proteins (e.g., IFNß and IFNγ)] was seen in the NAc, while decreased expression of cytokines (e.g., several ILs), chemokines [e.g., granulocyte-macrophage colony-stimulating factor (GMCSF), monocyte chemoattractant protein (MCP) MCP1, MIP3α], the chemokine ligand 5 (RANTES) and interferons (e.g., IFNß and IFNγ) in the HIP. Positive correlations were observed between cumulative fentanyl intake and expression of IL1ß and IL6 in the NAc, and significant negative correlations with fentanyl intake and IFN ß, IL2, IL5, IL12p70 and IL17 in the HIP. Few changes in OR expression was observed during early abstinence from fentanyl self-administration. Excitingly, the expression of the PRR, stimulator of interferon genes (STING) negatively correlated with cumulative fentanyl intake and significantly correlated to specific cytokines, chemokines and interferon proteins in the HIP. Although the CPu appears relatively invulnerable to changes in innate immune markers, the highest correlations between cumulative fentanyl intake with MAVS and/or STING was measured in the CPu. Our findings provide the first evidence of CNS innate immune responses and implicate STING as novel mechanistic targets of immunomodulation during short-term abstinence from fentanyl self-administration.

Advances in juvenile adjudicative competence: A 10-year update.

This article provides a comprehensive review of juvenile adjudicative competence (AC) literature published between 2010 and 2019. Publications included in this article are peer-reviewed and disseminate original research or provide new commentary on forensic evaluation, policy, or theory. The review is organized in the following sequence: (i) factors associated with juvenile AC, (ii) evaluating juvenile AC (assessment tools and techniques, quality of evaluations, evaluation recommendations), (iii) remediation (remediation recommendations), (iv) systemic issues (inconsistency in statutes and court processes, defense attorneys' concerns about AC, age-related issues, developmental immaturity), and (v) special topics (special populations, international research). Systemic processes and variability in statutes have contributed to current concerns regarding reliability of juvenile AC evaluation and remediation. Clear and consistent standards must be developed to address these problems. Continued research is necessary to clarify how to accurately assess juvenile AC and appropriately remediate those adjudicated incompetent. Practice and policy implications as well as future directions for research are discussed.

Dental professionals' experiences of managing children with carious lesions in their primary teeth - a qualitative study within the FiCTION randomised controlled trial.

BACKGROUND: The lack of evidence for the effective management of carious lesions in children's primary teeth has caused uncertainty for the dental profession and patients. Possible approaches include conventional and biological management alongside best practice prevention, and best practice prevention alone. The FiCTION trial assessed the effectiveness of these options, and included a qualitative study exploring dental professionals' (DPs) experiences of delivering the different treatment arms. This paper reports on how DPs managed children with carious lesions within FiCTION and how this related to their everyday experiences of doing dentistry. METHODS: Overall, 31 DPs from FiCTION-trained dental surgeries in four regions of the UK participated in semi-structured interviews about their experiences of the three treatment arms (conventional management of carious lesions and prevention (C + P), biological management of carious lesions and prevention (B + P) or prevention alone (PA)). A theoretical framework, drawing on social practice theory (SPT), was developed for analysis. RESULTS: Participants discussed perceived effectiveness of, and familiarity with, the three techniques. The C + P arm was familiar, but some participants questioned the effectiveness of conventional restorations. Attitudes towards the B + P arm varied in terms of familiarity, but once DPs were introduced to the techniques, this was seen as effective. While prevention was familiar, PA was described as ineffective. DPs manage children with carious lesions day-to-day, drawing on previous experience and knowledge of the child to provide what they view as the most appropriate treatment in the best interests of each child. Randomisation undermined these normal choices. Several DPs reported deviating from the trial arms in order to treat a patient in a particular way. Participants valued evidence-based dentistry, and expect to use the results of FiCTION to inform future practice. They anticipate continuing to use the full range of treatment options, and to personally select appropriate strategies for individual children. CONCLUSIONS: RCTs take place in the context of day-to-day practices of doing dentistry. DPs employ experiential and interpersonal knowledge to act in the best interests of their patients. Randomisation within a clinical trial can present a source of tension for DPs, which has implications for assuring individual equipoise in future trials.

Children and parents' perspectives on the acceptability of three management strategies for dental caries in primary teeth within the 'Filling Children's Teeth: Indicated or Not' (FiCTION) randomised controlled trial - a qualitative study.

BACKGROUND: The Filling Children's Teeth: Indicated Or Not? (FiCTION) randomised controlled trial (RCT) aimed to explore the clinical- and cost-effectiveness of managing dental caries in children's primary teeth. The trial compared three management strategies: conventional caries management with best practice prevention (C + P), biological management with best practice prevention (B + P) and best practice prevention alone (PA)-based approaches. Recently, the concept of treatment acceptability has gained attention and attempts have been made to provide a conceptual definition, however this has mainly focused on adults. Recognising the importance of evaluating the acceptability of interventions in addition to their effectiveness, particularly for multi-component complex interventions, the trial design included a qualitative component. The aim of this component was to explore the acceptability of the three strategies from the perspectives of the child participants and their parents. METHODS: Qualitative exploration, based on the concept of acceptability. Participants were children already taking part in the FiCTION trial and their parents. Children were identified through purposive maximum variation sampling. The sample included children from the three management strategy arms who had been treated and followed up; median (IQR) follow-up was at 33.8 (23.8, 36.7) months. Semi-structured interviews with thirteen child-parent dyads. Interviews were transcribed verbatim and analysed using a framework approach. RESULTS: Data saturation was reached after thirteen interviews. Each child-parent dyad took part in one interview together. The participants were eight girls and five boys aged 5-11 years and their parents. The children's distribution across the trial arms was: C + P n = 4; B + P n = 5; PA n = 4. Three key factors influenced the acceptability of caries management in primary teeth to children and parents: i) experiences of specific procedures within management strategies; ii) experiences of anticipatory dental anxiety and; iii) perceptions of effectiveness (particularly whether pain was reduced). These factors were underpinned by a fourth key factor: the notion of trust in the dental professionals - this was pervasive across all arms. CONCLUSIONS: Overall children and parents found each of the three strategies for the management of dental caries in primary teeth acceptable, with trust in the dental professional playing an important role.

The 5-HT2A Receptor (5-HT2AR) Regulates Impulsive Action and Cocaine Cue Reactivity in Male Sprague-Dawley Rats.

Impulsivity and the attentional orienting response to cocaine-associated cues (cue reactivity) promote relapse in cocaine-use disorder (CUD). A time-dependent escalation of cue reactivity (incubation) occurs during extended, forced abstinence from cocaine self-administration in rats. The investigational serotonin (5-HT) 5-HT2A receptor (5-HT2AR) antagonist/inverse agonist M100907 suppresses impulsive action, or the inability to withhold premature responses, and cocaine-seeking behaviors. The present preclinical study was designed to establish the potential for repurposing the Food and Drug Administration-approved selective 5-HT2AR antagonist/inverse agonist pimavanserin as a therapeutic agent to forestall relapse vulnerability in CUD. In male Sprague-Dawley rats, pimavanserin suppressed impulsive action (premature responses) measured in the 1-choice serial reaction time (1-CSRT) task, similarly to M100907. We also used the 1-CSRT task to establish baseline levels of impulsive action before cocaine self-administration and evaluation of cue reactivity (lever presses reinforced by the discrete cue complex previously paired with cocaine delivery). We observed an incubation of cocaine cue reactivity between day 1 and day 30 of forced abstinence from cocaine self-administration. Baseline levels of impulsive action predicted incubated levels of cocaine cue reactivity in late abstinence. We also found that baseline impulsive action predicted the effectiveness of pimavanserin to suppress incubated cue reactivity in late abstinence from cocaine self-administration at doses that were ineffective in early abstinence. These data suggest that integration of clinical measures of impulsive action may inform refined, personalized pharmacotherapeutic intervention for the treatment of relapse vulnerability in CUD.

Anterior insula activity regulates the associated behaviors of high fat food binge intake and cue reactivity in male rats.

Binge eating episodes are characterized by uncontrollable, excessive intake of food and are associated with binge eating disorder and some subtypes of obesity. One factor thought to contribute to binge episodes is a high level of reactivity to food-associated cues (i.e., cue reactivity). The insula is a neural node poised to regulate both binge eating and cue reactivity because of its prominent role in interpretation of internal and external cues. This work established a positive association between high fat food (HFF) binge intake and cue reactivity in male rats. Furthermore, we demonstrated that activation of the anterior insula suppressed both HFF binge intake and cue reactivity, without altering homeostatic intake of food. We further show that attenuation of HFF binge intake and cue reactivity is not due to decreased food-reward efficacy or deficits in motivation. Together, these data establish a key role for the anterior insula in the control of binge eating related-behaviors and support novel avenues for the treatment of binge eating.

Synthesis and activity of functionalizable derivatives of the serotonin (5-HT) 5-HT2A receptor (5-HT2AR) antagonist M100907.

The approach of tethering together two known receptor ligands, to be used as molecular probes for the study of G protein-coupled receptor (GPCR) systems, has proven to be a valuable approach. Selective ligands that possess functionality that can be used to link to other ligands, are useful in the development of novel antagonists and agonists. Such molecules can also be attached to reporter molecules, such as fluorophores, for the study of GPCR dimerization and its role in signaling. The highly selective serotonin (5-HT) 5-HT2A receptor (5-HT2AR) antagonist M100907 (volinanserin) is of clinical interest in the treatment of neurological and mental health disorders. Here, we synthesized the most active (+)-M100907 enantiomer as well as a series of derivatives that possessed either an alkyne or an azide. The triazole resulting from the dipolar cycloaddition of these groups did not interfere with the ability of the bivalent ligand to act as an antagonist. Thus, we have synthesized a number of compounds which will prove useful in elucidating the role of the 5-HT2AR in the central nervous system.

PPARγ agonism attenuates cocaine cue reactivity.

Cocaine use disorder is a chronic relapsing condition characterized by compulsive drug seeking and taking even after prolonged abstinence periods. Subsequent exposure to drug-associated cues can promote intense craving and lead to relapse in abstinent humans and rodent models. The responsiveness to these cocaine-related cues, or 'cue reactivity', can trigger relapse and cocaine-seeking behaviors; cue reactivity is measurable in cocaine-dependent humans as well as rodent models. Cue reactivity is thought to be predictive of cocaine craving and relapse. Here we report that PPARγ agonism during abstinence from cocaine self-administration reduced previously active lever pressing in Sprague Dawley rats during cue-reactivity tests, while administration of the PPARγ antagonist, GW9662, reversed this effect. PPARγ agonism also normalized nuclear ERK activity in the medial prefrontal cortex and hippocampus which was reversed with GW9662. Our results support the utility of PPARγ agonism as a relapse prevention strategy to maintain abstinence in the presence of cocaine-associated cues.

Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder.

Cocaine exhibits prominent abuse liability, and chronic abuse can result in cocaine use disorder with significant morbidity. Major advances have been made in delineating neurobiological mechanisms of cocaine abuse; however, effective medications to treat cocaine use disorder remain to be discovered. The present review will focus on the role of serotonin (5-HT; 5-hydroxytryptamine) neurotransmission in the neuropharmacology of cocaine and related abused stimulants. Extensive research suggests that the primary contribution of 5-HT to cocaine addiction is a consequence of interactions with dopamine (DA) neurotransmission. The literature on the neurobiological and behavioral effects of cocaine is well developed, so the focus of the review will be on cocaine with inferences made about other monoamine uptake inhibitors and releasers based on mechanistic considerations. 5-HT receptors are widely expressed throughout the brain, and several different 5-HT receptor subtypes have been implicated in mediating the effects of endogenous 5-HT on DA. However, the 5-HT2A and 5-HT2C receptors in particular have been implicated as likely candidates for mediating the influence of 5-HT in cocaine abuse as well as to traits (e.g., impulsivity) that contribute to the development of cocaine use disorder and relapse in humans. Lastly, new approaches are proposed to guide targeted development of serotonergic ligands for the treatment of cocaine use disorder.

Modifying Alcohol Consumption to Reduce Obesity: A Randomized Controlled Feasibility Study of a Complex Community-based Intervention for Men.

OBJECTIVES: Being obese and drinking more than 14 units of alcohol per week places men at very high risk of developing liver disease. This study assessed the feasibility of a trial to reduce alcohol consumption. It tested the recruitment strategy, engagement with the intervention, retention and study acceptability. METHODS: Men aged 35-64 years who drank >21 units of alcohol per week and had a BMI > 30 were recruited by two methods: from GP patient registers and by community outreach. The intervention was delivered by a face to face session followed by a series of text messages. Trained lay people (Study Coordinators) delivered the face to face session. Participants were followed up for 5 months from baseline to measure weekly alcohol consumption and BMI. RESULTS: The recruitment target of 60 was exceeded, with 69 men recruited and randomized. At baseline, almost all the participants (95%) exceeded the threshold for a 19-fold increase in the risk of dying from liver disease. The intervention was delivered with high fidelity. A very high follow-up rate was achieved (98%) and the outcomes for the full trial were measured. Process evaluation showed that participants responded as intended to key steps in the behaviour change strategy. The acceptability of the study methods was high: e.g. 80% of men would recommend the study to others. CONCLUSIONS: This feasibility study identified a group at high risk of liver disease. It showed that a full trial could be conducted to test the effectiveness and cost-effectiveness of the intervention. TRIAL REGISTRATION: Current controlled trials: ISRCTN55309164. TRIAL FUNDING: National Institute for Health Research Health Technology Assessment (NIHR HTA). SHORT SUMMARY: This feasibility study recruited 69 men at high risk of developing liver disease. The novel intervention, to reduce alcohol consumption through the motivation of weight loss, was well received. A very high follow-up rate was achieved. Process evaluation showed that participants engaged with key components of the behaviour change strategy.

Sacral Neuromodulation for the Treatment of Retention in Partial Sacrectomy Patients.

INTRODUCTION: Sacral chordoma is a rare malignant tumor arising from remnants of the notochord. Due to its propensity for recurrence, the treatment of choice is surgical resection. Orthopedic and neurosurgical literature describe bladder dysfunction as prevalent in these patients, specifically urinary incontinence, however urologic literature is lacking in the exact nature of this dysfunction. Thus far, Sacral Nerve Stimulation (SNS) has not been described as a treatment option for these patients. PRESENTATION OF CASE: We describe a 36-year-old female who underwent midsacral resection (S3 and below) for a sacrococcygeal chordoma. She suffered from postoperative urinary incontinence and incomplete emptying requiring intermittent catheterization. Urodynamic evaluation showed detrusor hyporeflexia with nonobstructive urinary retention. She underwent InterStim® (Minneapolis, MN) placement resulting in return of spontaneous voiding and resolution of retention. DISCUSSION: SNS has been FDA approved for treatment of nonobstructive urinary retention since 1999. It has yet to be described as an effective treatment option in patients who have undergone sacral resection and suffer from prolonged postoperative nonobstructive urinary retention. Operative reports may not contain sufficient detail to confirm whether one or both S3 nerve roots are intact. Thus, it is mandatory to perform a bilateral nerve evaluation to verify integrity of the S3 nerve roots in this cohort of patients. This can present a technical challenge, as some of the usual landmarks are surgically absent. However, we have shown that the procedure is feasible and effective after partial sacral resection. CONCLUSION: We are the first to report the successful use of SNS to treat nonobstructive urinary retention after partial sacral resection. Additional patients and long term follow-up will be required to support consistent usage of neuromodulation in this patient population.

What is the relationship between elements of ICU treatment and memories after discharge in adult ICU survivors?

OBJECTIVES: Patients admitted to an intensive care unit (ICU) often experience distressing memories during recovery that have been associated with poor psychological and cognitive outcomes. The aim of this literature review was to synthesise the literature reporting on relationships between elements of ICU treatment and memories after discharge in adult ICU survivors. REVIEW METHOD USED: Integrative review methods were used to systematically search, select, extract, appraise and summarise current knowledge from the available research and identify gaps in the literature. DATA SOURCES: The following electronic databases were systematically searched: PubMed, Ovid EMBASE, EBSCOhost CINAHL, PsycINFO and Cochrane Central Register of Controlled Trials. Additional studies were identified through searches of bibliographies. Original quantitative research articles written in English that were published in peer-review journals were included. REVIEW METHODS: Data extracted from studies included authors, study aims, population, sample size and characteristics, methods, ICU treatments, ICU memory definitions, data collection strategies and findings. Study quality assessment was based on elements of the Critical Appraisal Skills Programme using the checklists developed for randomised controlled trials and cohort studies. RESULTS: Fourteen articles containing data from 13 studies met the inclusion criteria and were included in the final analysis. The relatively limited evidence about the association between elements of ICU treatment and memories after ICU discharge suggest that deep sedation, corticoids and administration of glucose 50% due to hypoglycaemia contribute to the development of delusional memories and amnesia of ICU stay. CONCLUSIONS: The body of literature on the relationship between elements of ICU treatment and memories after ICU discharge is small and at its early stages. Larger studies using rigorous study design are needed in order to evaluate the effects of different elements of ICU treatment on the development of memories of the ICU during recovery.

Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior.

Serotonin (5-hydroxytryptamine; 5-HT) signaling through the 5-HT(2C) receptor (5-HT(2C)R) is essential in normal physiology, whereas aberrant 5-HT(2C)R function is thought to contribute to the pathogenesis of multiple neural disorders. The 5-HT(2C)R interacts with specific protein partners, but the impact of such interactions on 5-HT(2C)R function is poorly understood. Here, we report convergent cellular and behavioral data that the interaction between the 5-HT(2C)R and protein phosphatase and tensin homolog (PTEN) serves as a regulatory mechanism to control 5-HT(2C)R-mediated biology but not that of the closely homologous 5-HT(2A)R. A peptide derived from the third intracellular loop of the human 5-HT(2C)R [3L4F (third loop, fourth fragment)] disrupted the association, allosterically augmented 5-HT(2C)R-mediated signaling in live cells, and acted as a positive allosteric modulator in rats in vivo. We identified the critical residues within an 8 aa fragment of the 3L4F peptide that maintained efficacy (within the picomolar range) in live cells similar to that of the 3L4F peptide. Last, molecular modeling identified key structural features and potential interaction sites of the active 3L4F peptides against PTEN. These compelling data demonstrate the specificity and importance of this protein assembly in cellular events and behaviors mediated by 5-HT(2C)R signaling and provide a chemical guidepost to the future development of drug-like peptide or small-molecule inhibitors as neuroprobes to study 5-HT(2C)R allostery and therapeutics for 5-HT(2C)R-mediated disorders.