Competition between emotional faces in visuospatial working memory.

Visuospatial working memory (VSWM) helps track the identity and location of people during social interactions. Previous work showed better VSWM when all faces at encoding displayed a happy compared to an angry expression, reflecting a prosocial preference for monitoring who was where. However, social environments are not typically uniform, and certain expressions may more strongly compete for and bias face monitoring according to valence and/or arousal properties. Here, we used heterogeneous encoding displays in which two faces shared one emotion and two shared another, and asked participants to relocate a central neutral probe face after a blank delay. When considering the emotion of the probed face independently of the co-occurring emotion at encoding, an overall happy benefit was replicated. However, accuracy was modulated by the nonprobed emotion, with a relocation benefit for angry over sad, happy over fearful, and sad over happy faces. These effects did not depend on encoding fixation time, stimulus arousal, perceptual similarity, or response bias. Thus, emotional competition for faces in VSWM is complex and appears to rely on more than simple arousal- or valence-biased mechanisms. We propose a "social value (SV)" account to better explain when and why certain emotions may be prioritized in VSWM. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Autologous bone marrow mononuclear cells to treat severe traumatic brain injury in children.

Autologous bone marrow mononuclear cells (BMMNCs) infused after severe traumatic brain injury have shown promise for treating the injury. We evaluated their impact in children, particularly their hypothesized ability to preserve the blood-brain barrier and diminish neuroinflammation, leading to structural CNS preservation with improved outcomes. We performed a randomized, double-blind, placebo-sham-controlled Bayesian dose-escalation clinical trial at two children's hospitals in Houston, TX and Phoenix, AZ, USA (NCT01851083). Patients 5-17 years of age with severe traumatic brain injury (Glasgow Coma Scale score ≤ 8) were randomized to BMMNC or placebo (3:2). Bone marrow harvest, cell isolation and infusion were completed by 48 h post-injury. A Bayesian continuous reassessment method was used with cohorts of size 3 in the BMMNC group to choose the safest between two doses. Primary end points were quantitative brain volumes using MRI and microstructural integrity of the corpus callosum (diffusivity and oedema measurements) at 6 months and 12 months. Long-term functional outcomes and ventilator days, intracranial pressure monitoring days, intensive care unit days and therapeutic intensity measures were compared between groups. Forty-seven patients were randomized, with 37 completing 1-year follow-up (23 BMMNC, 14 placebo). BMMNC treatment was associated with an almost 3-day (23%) reduction in ventilator days, 1-day (16%) reduction in intracranial pressure monitoring days and 3-day (14%) reduction in intensive care unit (ICU) days. White matter volume at 1 year in the BMMNC group was significantly preserved compared to placebo [decrease of 19 891 versus 40 491, respectively; mean difference of -20 600, 95% confidence interval (CI): -35 868 to -5332; P = 0.01], and the number of corpus callosum streamlines was reduced more in placebo than BMMNC, supporting evidence of preserved corpus callosum connectivity in the treated groups (-431 streamlines placebo versus -37 streamlines BMMNC; mean difference of -394, 95% CI: -803 to 15; P = 0.055), but this did not reach statistical significance due to high variability. We conclude that autologous BMMNC infusion in children within 48 h after severe traumatic brain injury is safe and feasible. Our data show that BMMNC infusion led to: (i) shorter intensive care duration and decreased ICU intensity; (ii) white matter structural preservation; and (iii) enhanced corpus callosum connectivity and improved microstructural metrics.

Large-scale analysis of cell-cell communication reveals angiogenin-dependent tumor progression in clear cell renal cell carcinoma.

Cellular crosstalk in the tumor microenvironment (TME) is still largely uncharacterized, while it plays an essential role in shaping immunosuppression or anti-tumor response. Large-scale analyses are needed to better decipher cell-cell communication in cancer. In this work, we used original and publicly available single-cell RNA sequencing (scRNAseq) data to characterize in-depth the communication networks in human clear cell renal cell carcinoma (ccRCC). We identified 50 putative communication channels specifically used by cancer cells to interact with other cells, including two novel angiogenin-mediated interactions. Expression of angiogenin and its receptors was validated at the protein level in primary ccRCC. Mechanistically, angiogenin enhanced ccRCC cell line proliferation and down-regulated secretion of IL-6, IL-8, and MCP-1 proinflammatory molecules. This study provides novel biological insights into molecular mechanisms of ccRCC, and suggests angiogenin and its receptors as potential therapeutic targets in clear cell renal cancer.

Paraneoplastic pemphigus uncovers distinct clinical and biological phenotypes of western unicentric Castleman disease.

Unicentric Castleman disease (UCD) is a lymphoproliferative disease of unknown cause. Paraneoplastic pemphigus (PNP) is a major complication shown to be associated with a poor prognosis, with particular severity in patients with bronchiolitis obliterans (BO). This study describes the clinical and biological characteristics of UCD-PNP patients in a large Western cohort. A total of 148 patients diagnosed with UCD were identified, including 14 patients with a defined PNP. PNP was significantly associated with myasthenia gravis (MG) and FDC sarcoma during follow-up (FDCS). PNP was also significantly associated with reduced survival. These data, together with a multivariate analysis by principal components, led to the identification of UCD-PNP as a group at risk of MG, FDCS and death. PDGFRB sequencing performed on UCD lesions from six patients found the gain-of-function p.N666S variant in two. Interestingly, both patients had hyaline-vascular UCD subtype, were in the UCD-PNP subgroup and had FDCS. Sera from 25 UCD-PNP patients and 6 PNP patients without UCD were tested for PNP-associated autoantibodies. Sera from UCD-PNP patients had a strong reactivity against the N-terminal domain of recombinant periplakin (rPPL, 82%) and showed reactivity against at least two domains of rPPL. These features were not found in patients with UCD alone or in the PNP group without UCD. These data indicate that UCD-PNP patients belong to a subgroup sharing strong clinical and biological identity that might help to decipher the different dynamics of UCD natural history.

Attentional load effects on emotional content in face working memory.

This study investigated the role of attentional resources in processing emotional faces in working memory (WM). Participants memorised two face arrays with the same emotion but different identities and were required to judge whether the test face had the same identity as one of the previous faces. Concurrently during encoding and maintenance, a sequence of high- or low-pitched tones (high load) or white noise bursts (low load) was presented, and participants were required to count how many low-tones were heard. Experiments 1 and 2 used an emotional and neutral test face, respectively. The results revealed a significant WM impairment for sad and angry faces in the high-load versus low-load condition but not for happy faces. In Experiment 1, participants remembered happy faces better than other emotional faces. In contrast, Experiment 2 showed that performance was poorer for happy than sad faces but not for angry faces. This evidence suggests that depleting attentional resources has less impact on WM for happy faces than other emotional faces, but also that differential effects on WM for emotional faces depend on the presence or absence of emotion in the probe face at retrieval.

Autologous cellular therapy for cerebral palsy: a randomized, crossover trial.

We examined an autologous mononuclear-cell-therapy-based approach to treat cerebral palsy using autologous umbilical cord blood or bone-marrow-derived mononuclear cells. The primary objective was to determine if autologous cells are safe to administer in children with cerebral palsy. The secondary objectives were to determine if there was improvement in motor function of patients 12 months after infusion using the Gross Motor Function Measure and to evaluate impact of treatment on corticospinal tract microstructure as determined by radial diffusivity measurement. This Phase 1/2a trial was a randomized, blinded, placebo-controlled, crossover study in children aged 2-10 years of age with cerebral palsy enrolled between November 2013 and November 2016. Participants were randomized to 2:1 treatment:placebo. Treatment was either autologous bone-marrow-derived mononuclear cells or autologous umbilical cord blood. All participants who enrolled and completed their baseline visit planned to return for follow-up visits at 6 months, 12 months and 24 months after the baseline visit. At the 12-month post-treatment visit, participants who originally received the placebo received either bone-marrow-derived mononuclear cell or umbilical cord blood treatment. Twenty participants were included; 7 initially randomized to placebo, and 13 randomized to treatment. Five participants randomized to placebo received bone-marrow-derived mononuclear cells, and 2 received umbilical cord blood at the 12-month visit. None of the participants experienced adverse events related to the stem cell infusion. Cell infusion at the doses used in our study did not dramatically alter motor function. We observed concordant bilateral changes in radial diffusivity in 10 of 15 cases where each corticospinal tract could be reconstructed in each hemisphere. In 60% of these cases (6/10), concordant decreases in bilateral corticospinal tract radial diffusivity occurred post-treatment. In addition, 100% of unilateral corticospinal tract cases (3/3) exhibited decreased corticospinal tract radial diffusivity post-treatment. In our discordant cases (n = 5), directionality of changes in corticospinal tract radial diffusivity appeared to coincide with handedness. There was a significant improvement in corticospinal tract radial diffusivity that appears related to handedness. Connectivity strength increased in either or both pathways (corticio-striatal and thalamo-cortical) in each participant at 12 months post-treatment. These data suggest that both stem cell infusions are safe. There may be an improvement in myelination in some groups of patients that correlate with small improvements in the Gross Motor Function Measure scales. A larger autologous cord blood trial is impractical at current rates of blood banking. Either increased private banking or matched units would be required to perform a larger-scale trial.

Increased perceptual distraction and task demand enhances gaze and non-biological cuing effects.

This study aims to improve understanding of how distracting information and target task demands influence the strength of gaze and non-biological (arrow and moving line) cuing effects. Using known non-predictive central cues, we manipulated the degree of distraction from additional information presented on the other side of the target, and target task difficulty. In Experiment 1, we used the traditional unilateral cuing task, where participants state the location of an asterisk and the non-target location is empty (no distraction). Experiment 2 comprised a harder localisation task (which side contains an embedded oddball item) and presented distracting target-related information on the other side. In Experiment 3, we used a discrimination task (upright or inverted embedded T) with distracter information that was unrelated or related to the target (low vs. high distraction, respectively). We found that the magnitude of cuing scaled with the degree of combined distraction and task demands, increasing up to six-fold from Experiments 1 and 2 to the high-distraction condition in Experiment 3. Thus, depleting attentional resources in this manner appears to weaken the ability to ignore uninformative directional cues. Findings are discussed within the framework of a resource-limited account of cue inhibition.

C-tag TNF: a reporter system to study TNF shedding.

TNF is a highly pro-inflammatory cytokine that contributes not only to the regulation of immune responses but also to the development of severe inflammatory diseases. TNF is synthesized as a transmembrane protein, which is further matured via proteolytic cleavage by metalloproteases such as ADAM17, a process known as shedding. At present, TNF is mainly detected by measuring the precursor or the mature cytokine of bulk cell populations by techniques such as ELISA or immunoblotting. However, these methods do not provide information on the exact timing and extent of TNF cleavage at single-cell resolution and they do not allow the live visualization of shedding events. Here, we generated C-tag TNF as a genetically encoded reporter to study TNF shedding at the single-cell level. The functionality of the C-tag TNF reporter is based on the exposure of a cryptic epitope on the C terminus of the transmembrane portion of pro-TNF on cleavage. In both denatured and nondenatured samples, this epitope can be detected by a nanobody in a highly sensitive and specific manner only upon TNF shedding. As such, C-tag TNF can successfully be used for the detection of TNF cleavage in flow cytometry and live-cell imaging applications. We furthermore demonstrate its applicability in a forward genetic screen geared toward the identification of genetic regulators of TNF maturation. In summary, the C-tag TNF reporter can be employed to gain novel insights into the complex regulation of ADAM-dependent TNF shedding.

A cross-cultural investigation into the influence of eye gaze on working memory for happy and angry faces.

Previous long-term memory (LTM) research found that angry faces were more poorly recognised when encoded with averted vs. direct gaze, while memory for happy faces was unaffected by gaze. Contrastingly, working memory (WM) accuracy for angry faces was unaffected by gaze, but WM was enhanced for happy faces with averted vs. direct gaze. Because the LTM study was conducted in an Eastern culture (Japan) with Japanese faces, while the WM study was conducted in a Western culture (UK) with Caucasian faces, here we investigated WM further to examine whether gaze effects diverge due to cultural variation between the faces and participants. When Western participants viewed Japanese faces (Experiment 1), the happy-averted gaze advantage in WM was replicated. In contrast, Japanese participants viewing Caucasian faces (Experiment 2a) showed poorer WM for angry faces with averted vs. direct gaze, and no influence of gaze on WM for happy faces. When Japanese participants viewed Japanese faces (Experiment 2b), gaze did not modulate WM. Therefore, the way in which expression and gaze interact to influence face WM does not appear to rely on the specific memory system engaged, but instead may be attributed to cultural differences in display rules between Eastern and Western cultures.

Awareness, Policy, Privacy, and More: Post-Secondary Students Voice Their Solutions to Cyberbullying.

This paper discusses solutions to cyberbullying posed by post-secondary students from four Canadian universities. The qualitative data used in this analysis were drawn from one open-ended question on an online student survey completed by 1458 undergraduate students, as well as 10 focus group transcripts involving a total of 36 students. Seven key themes emerged: awareness and education; policy; protecting one's privacy; technology-based solutions; empowering better choices and responses; university culture; and disciplinary measures. The findings show that post-secondary institutions need to make preventing and curtailing cyberbullying more of a priority within their campus communities, including engaging in responsive consultation with key stakeholder groups, such as students, to develop meaningful solutions.

Ability of the PILOT score to predict 6-month functional outcome in pediatric patients with moderate-severe traumatic brain injury.

PURPOSE: To assess the Pediatric Intensity Level of Therapy (PILOT) score alone and in combination with Emergency Department (ED) GCS and Rotterdam score of initial head CT to predict functional outcomes in children with traumatic brain injury (TBI). METHODS: Children (n=108) aged 31months-15years with moderate to severe TBI were prospectively enrolled at two sites. The ability of PILOT, ED GCS, and Rotterdam scores to predict the 6-month Pediatric Injury Functional Outcome Scale (PIFOS) was evaluated using multivariable regression models with enrollment site, age, and sex as covariates. RESULTS: PILOT total (sum) score was more predictive of PIFOS (R2=0.23) compared to mean (R2 = 0.20) or peak daily PILOT scores (R2=0.11). PILOT total score predicted PIFOS better than ED GCS (R2=0.01) or Rotterdam score (R2=0.06) and was similar to PILOT, ED GCS, and Rotterdam score combined. PILOT total score performed better in patients with intracranial pressure monitors (n=30, R2=0.28, slope=0.30) than without (n=78, R2=0.09, slope=0.36). CONCLUSIONS: The PILOT score correlated moderately with functional outcome following TBI and outperformed other common predictors. PILOT may be a useful predictor or moderator of functional outcomes. LEVEL OF EVIDENCE: Prognosis study, Level II.

Task cues lead to item-level backward inhibition with univalent stimuli and responses.

Backward inhibition may aid our ability to switch between tasks by counteracting the tendency to repeat a recently performed task. Current theory asserts that conflict between tasks during performance plays a key role in inducing the effect. However, a study by Costa and Friedrich suggests that backward inhibition might occur without this type of conflict being present. To better understand the mechanisms underlying backward inhibition, we investigated the roles of between-task conflict, task-based instructions, and task cues. Experiment 1 tentatively supported the view that conflict between tasks is not necessary for backward inhibition to be present, and suggested that either the use of task-based instructions or the provision of specific task cues might be sufficient to generate the effect. Experiment 2 ruled out task-based instruction as a likely cause of backward inhibition in this context. Experiment 3 showed that the provision of task cues was sufficient to drive a significant backward inhibition effect, but only when stimuli and responses (as well as tasks) repeated. Overall, these results indicate that between-task conflict during performance is not necessary for backward inhibition to be applied, and that task cues have a key role in generating the effect.

High-latitude warming initiated the onset of the last deglaciation in the tropics.

Atmospheric greenhouse gas concentrations are thought to have synchronized global temperatures during Pleistocene glacial-interglacial cycles, yet their impact relative to changes in high-latitude insolation and ice-sheet extent remains poorly constrained. Here, we use tropical glacial fluctuations to assess the timing of low-latitude temperature changes relative to global climate forcings. We report 10Be ages of moraines in tropical East Africa and South America and show that glaciers reached their maxima at ~29 to 20 ka, during the global Last Glacial Maximum. Tropical glacial recession was underway by 20 ka, before the rapid CO2 rise at ~18.2 ka. This "early" tropical warming was influenced by rising high-latitude insolation and coincident ice-sheet recession in both polar regions, which lowered the meridional thermal gradient and reduced tropical heat export to the high latitudes.

Clinical parameters affecting multipotent adult progenitor cells in vitro.

BACKGROUND: Human multipotent adult progenitor cells (MAPC®) are an emerging therapy for traumatic brain injury (TBI); however, clinically translating a therapy involves overcoming many factors in vivo which are not present in pre-clinical testing. In this study we examined clinical parameters in vitro that may impact cell therapy efficacy. METHODS: MAPC were infused through varying gauged needles and catheters with and without chlorhexidine, and their viability tested with trypan blue exclusion. MAPC were co-cultured with phenytoin and celecoxib at relevant clinical concentrations for 1 h and 24 h. Anti-inflammatory potency was tested using a stimulated rat splenocyte co-culture and ELISA for TNF-α production. MAPC were cultured under different osmolar concentrations and stained with propidium iodide for viability. Anti-inflammatory potency was tested by co-culture of MAPC with naïve lymphocytes activated by CD3/CD28 beads, and Click-iT® Plus EdU was used to quantify proliferation by flow cytometry. RESULTS: The mean viability of the MAPC infused via needles was 95 ± 1%; no difference was seen with varying flow rate, but viability was notably reduced by chlorhexidine. MAPC function was not impaired by co-culture with phenytoin, celecoxib, or combination with both. Co-culture with phenytoin showed a decrease in TNF-α production as compared to the MAPC control. MAPC cultured at varying osmolar concentrations all had viabilities greater than 90% with no statistical difference between them. Co-culture of MAPC with CD3/CD28 activated PBMCs showed a significant reduction in proliferation as measured by EdU uptake. DISCUSSION: Needle diameter, phenytoin, celecoxib, and a relevant range of osmolarities do not impair MAPC viability or anti-inflammatory potency in vitro.

Gallstone Pancreatitis: Admission Versus Normal Cholecystectomy-a Randomized Trial (Gallstone PANC Trial).

INTRODUCTION: Early cholecystectomy shortly after admission for mild gallstone pancreatitis has been proposed based on observational data. We hypothesized that cholecystectomy within 24 hours of admission versus after clinical resolution of gallstone pancreatitis that is predicted to be mild results in decreased length-of-stay (LOS) without an increase in complications. METHODS: Adults with predicted mild gallstone pancreatitis were randomized to cholecystectomy with cholangiogram within 24 hours of presentation (early group) versus after clinical resolution (control) based on abdominal exam and normalized laboratory values. Primary outcome was 30-day LOS including readmissions. Secondary outcomes were time to surgery, endoscopic retrograde cholangiopancreatography (ERCP) rates, and postoperative complications. Frequentist and Bayesian intention-to-treat analyses were performed. RESULTS: Baseline characteristics were similar in the early (n = 49) and control (n = 48) groups. Early group had fewer ERCPs (15% vs 29%, P = 0.038), faster time to surgery (16 h vs 43 h, P < 0.005), and shorter 30-day LOS (50 h vs 77 h, RR 0.68 95% CI 0.65 - 0.71, P < 0.005). Complication rates were 6% in early group versus 2% in controls (P = 0.613), which included recurrence/progression of pancreatitis (2 early, 1 control) and a cystic duct stump leak (early). On Bayesian analysis, early cholecystectomy has a 99% probability of reducing 30-day LOS, 93% probability of decreasing ERCP use, and 72% probability of increasing complications. CONCLUSION: In patients with predicted mild gallstone pancreatitis, cholecystectomy within 24 hours of admission reduced rate of ERCPs, time to surgery, and 30-day length-of-stay. Minor complications may be increased with early cholecystectomy. Identification of patients with predicted mild gallstone pancreatitis in whom early cholecystectomy is safe warrants further investigation.

Facilitated group work for people with long-term conditions: a systematic review of benefits from studies of group-work interventions.

BACKGROUND: About 15.4 million people in the UK live with a long-term condition. Of the health and social care spend, 70% is invested in caring for this population. Evidence suggests that group-work interventions offer patient support, improved outcomes, and reduce the costs of care. AIM: To review the current evidence base examining the effectiveness of group work in long-term physical disease where such groups are facilitated by healthcare professionals. DESIGN AND SETTING: Systematic review and narrative synthesis of studies of group-work interventions led by health professionals for adults with specified long-term illnesses. METHOD: MEDLINE, EMBASE, PsycINFO, and Cochrane databases were systematically searched using terms relating to group work and long-term conditions. Studies were included if they were randomised controlled trials (RCTs) with a control group that did not include group work. RESULTS: The 14 included studies demonstrated a high degree of heterogeneity in terms of participant characteristics, interventions, and outcome measures and were of varying quality. The studies demonstrated some statistically significant improvements in pain, psychological outcomes, self-efficacy, self-care, and quality of life resulting from intervention. CONCLUSION: This review demonstrates significant benefits resulting from group participation, in adults with long-term disease. Results were mixed and some benefits were short-lived. Nevertheless, these results suggest that group work should be more widely used in the management and support of adults with long-term illness. There is a need for larger and better-quality studies to explore this potentially important area further.

Effects of induced sad mood on facial emotion perception in young and older adults.

Older adults perceive less intense negative emotion in facial expressions compared to younger counterparts. Prior research has also demonstrated that mood alters facial emotion perception. Nevertheless, there is little evidence which evaluates the interactive effects of age and mood on emotion perception. This study investigated the effects of sad mood on younger and older adults' perception of emotional and neutral faces. Participants rated the intensity of stimuli while listening to sad music and in silence. Measures of mood were administered. Younger and older participants' rated sad faces as displaying stronger sadness when they experienced sad mood. While younger participants showed no influence of sad mood on happiness ratings of happy faces, older adults rated happy faces as conveying less happiness when they experienced sad mood. This study demonstrates how emotion perception can change when a controlled mood induction procedure is applied to alter mood in young and older participants.

Barriers block the effect of joint attention on working memory: Perspective taking matters.

Joint focus of attention between two individuals can influence the way that observers attend, encode, and value items. Using a nonpredictive gaze cuing task we previously found that working memory (WM) was better for jointly attended (validly cued) versus invalidly cued colored squares. Here we examine whether this influence of gaze on WM is driven by observers sharing the perspective of the face cue (mental state account), or simply by increased attention to the cued location (social attention account). To manipulate perspective taking, a closed barrier obstructed the cue face's view of the memoranda, while an open barrier allowed the cue face to "see" the colors. A central cue face flanked by two identical barriers looked left or right, followed 500 ms later by colored squares for encoding which appeared equally often in the validly and invalidly cued locations. After a blank 1,000 ms maintenance interval, participants stated whether a probe color was present or not in the preceding display. When the barrier was open, WM was significantly impaired for invalidly versus validly cued items. When the barrier was closed, the effect of gaze cues on WM was abolished. In contrast, further experiments showed a significant cuing effect on the speed of simple target localization and color discrimination regardless of barrier type. These findings support the mental state account of joint attention in WM, whereby the attentional focus of another alters WM via higher level engagement with the second person perspective. A goal-specific model of perspective taking is proposed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes.

BACKGROUND: Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown. The current study investigated metformin-induced GLP-1 secretion and its contribution to the overall glucose-lowering effect of metformin and underlying mechanisms in patients with type 2 diabetes. METHODS: Twelve patients with type 2 diabetes were included in this placebo-controlled, double-blinded study. On 4 separate days, the patients received metformin (1,500 mg) or placebo suspended in a liquid meal, with subsequent i.v. infusion of the GLP-1 receptor antagonist exendin9-39 (Ex9-39) or saline. During 240 minutes, blood was sampled. The direct effect of metformin on GLP-1 secretion was tested ex vivo in human ileal and colonic tissue with and without dorsomorphin-induced inhibiting of the AMPK activity. RESULTS: Metformin increased postprandial GLP-1 secretion compared with placebo (P = 0.014), and the postprandial glucose excursions were significantly smaller after metformin + saline compared with metformin + Ex9-39 (P = 0.004). Ex vivo metformin acutely increased GLP-1 secretion (colonic tissue, P < 0.01; ileal tissue, P < 0.05), but the effect was abolished by inhibition of AMPK activity. CONCLUSIONS: Metformin has a direct and AMPK-dependent effect on GLP-1-secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to metformin's glucose-lowering effect and mode of action. TRIAL REGISTRATION: NCT02050074 (https://clinicaltrials.gov/ct2/show/NCT02050074). FUNDING: This study received grants from the A.P. Møller Foundation, the Novo Nordisk Foundation, the Danish Medical Association research grant, the Australian Research Council, the National Health and Medical Research Council, and Pfizer Inc.

Cligosiban, A Novel Brain-Penetrant, Selective Oxytocin Receptor Antagonist, Inhibits Ejaculatory Physiology in Rodents.

INTRODUCTION: Few treatments are available for men with premature ejaculation (PE); oxytocin (OT) receptor antagonism in the central nervous system (CNS) is a potential new approach. AIM: To determine if cligosiban selectively inhibits human OT receptors, penetrates the CNS, shows pharmacology in the CNS, and effects ejaculatory physiology in pre-clinical systems. METHODS: Experiments complied with United Kingdom legislation and were subject to local ethical review. In vitro potency and selectivity of cligosiban was assessed using recombinant and native OT receptor systems including both neuronal and non-neuronal cell types. Selectivity was determined over neighboring V1A, V1B, and V2 vasopressin receptors using a combination of recombinant and native vasopressin receptor assay systems. To determine an effect on central OT receptors and on ejaculation, cligosiban was evaluated in 2 anesthetized rat models-the electromyography model of ejaculatory physiology and a model of OT-mediated CNS neuronal firing. The CNS penetration of cligosiban was also determined by measuring cerebrospinal fluid and plasma drug concentrations following an intravenous (IV) infusion in rats. MAIN OUTCOME MEASURE: These were functional measures of pharmacology in vitro, in cell lines and tissues, and in vivo in rats. RESULTS: Cligosiban is a potent OT receptor antagonist, with a base dissociation constant of 5.7 nmol/L against native human uterine smooth muscle cell OT receptors. Cligosiban displays similar antagonistic potency against human recombinant and rat native OT receptors, including neuronal OT receptors. Cligosiban demonstrates >100-fold selectivity over human V1A, V1B, and V2 vasopressin receptors. In the electromyography model, cligosiban (0.9 mg/kg, IV bolus) reduced the bulbospongiosum burst pattern and contraction amplitude associated with ejaculation. In the anesthetized CNS neuronal firing model, the same dosing regimen of cligosiban (0.9 mg/kg IV bolus) modulated the OT-mediated response in the nucleus tractus solitarius. After systemic dosing to rats, cligosiban showed good CNS penetration. CLINICAL IMPLICATIONS: As the first highly selective and centrally penetrant OT receptor antagonist, cligosiban represents a promising compound to test the clinical hypothesis that antagonism of central OT receptors may be of therapeutic benefit in the treatment of PE. STRENGTH & LIMITATIONS: The pharmacology and selectivity of cligosiban is determined using functional assays in recombinant cell lines, native cell lines, and tissue. Functional outcomes in in vivo systems are linked to CNS measures of pharmacology. The translation of the animal models of ejaculation to PE in man is unproven. CONCLUSION: Cligosiban, a potent, selective OT receptor antagonist, demonstrated CNS penetration and pharmacology and, using the same dosing regimen, inhibited apomorphine-induced ejaculation in rats. Cligosiban is a promising compound to test the clinical hypothesis that antagonism of central OT receptors may be of therapeutic benefit in the treatment of PE. Wayman C, Russell R, Tang K, et al. Cligosiban, A Novel Brain Penetrant Selective Oxytocin Receptor Antagonist, Inhibits Ejaculatory Physiology in Rodents. J Sex Med 2018;15:1698-1706.