Pattern separation of fear extinction memory.

While fear generalizes widely, extinction is stimulus-specific. Using a hybrid conditioning/episodic memory paradigm, subjects encoded nonrepeating category exemplars during fear conditioning and extinction. Twenty-four hours later, a surprise memory test included old, similar, and novel category exemplars. Results showed strong dissociation between pattern completion (generalization) and pattern separation (discrimination) in episodic memory for items encoded during fear conditioning versus extinction, respectively. These data suggest that directly threat-conditioned stimuli are better recognized at the expense of mnemonic precision, whereas discrimination is enhanced for extinguished stimuli. Overly precise extinction memory may be a contributing factor to fear relapse.

The neurobiology of Pavlovian safety learning: Towards an acquisition-expression framework.

Safety learning creates associations between conditional stimuli and the absence of threat. Studies of human fear conditioning have accumulated evidence for the neural signatures of safety over various paradigms, aligning on several common brain systems. While these systems are often interpreted as underlying safety learning in a generic sense, they may instead reflect the expression of learned safety, pertaining to processes of fear inhibition, positive affect, and memory. Animal models strongly suggest these can be separable from neural circuits implicated in the conditioning process itself (or safety acquisition). While acquisition-expression distinctions are ubiquitous in behavioural science, this lens has not been applied to safety learning, which remains a novel area in the field. In this mini-review, we overview findings from prevalent safety paradigms in humans, and synthesise these with insights from animal models to propose that the neurobiology of safety learning be conceptualised along an acquisition-expression model, with the aim of stimulating richer brain-based characterisations of this important process.

Methodological implications of sample size and extinction gradient on the robustness of fear conditioning across different analytic strategies.

Fear conditioning paradigms are critical to understanding anxiety-related disorders, but studies use an inconsistent array of methods to quantify the same underlying learning process. We previously demonstrated that selection of trials from different stages of experimental phases and inconsistent use of average compared to trial-by-trial analysis can deliver significantly divergent outcomes, regardless of whether the data is analysed with extinction as a single effect, as a learning process over the course of the experiment, or in relation to acquisition learning. Since small sample sizes are attributed as sources of poor replicability in psychological science, in this study we aimed to investigate if changes in sample size influences the divergences that occur when different kinds of fear conditioning analyses are used. We analysed a large data set of fear acquisition and extinction learning (N = 379), measured via skin conductance responses (SCRs), which was resampled with replacement to create a wide range of bootstrapped databases (N = 30, N = 60, N = 120, N = 180, N = 240, N = 360, N = 480, N = 600, N = 720, N = 840, N = 960, N = 1080, N = 1200, N = 1500, N = 1750, N = 2000) and tested whether use of different analyses continued to produce deviating outcomes. We found that sample size did not significantly influence the effects of inconsistent analytic strategy when no group-level effect was included but found strategy-dependent effects when group-level effects were simulated. These findings suggest that confounds incurred by inconsistent analyses remain stable in the face of sample size variation, but only under specific circumstances with overall robustness strongly hinging on the relationship between experimental design and choice of analyses. This supports the view that such variations reflect a more fundamental confound in psychological science-the measurement of a single process by multiple methods.

Cortico-Striatal Activity Characterizes Human Safety Learning via Pavlovian Conditioned Inhibition.

Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and security-seeking behaviors. Precisely how safety learning is mediated at the level of underlying brain systems, particularly in humans, remains unclear. Here, we integrated a novel Pavlovian conditioned inhibition task with ultra-high field (7 Tesla) fMRI to examine the neural basis of safety learning in 49 healthy participants. In our task, participants were conditioned to two safety signals: a conditioned inhibitor that predicted threat omission when paired with a known threat signal (A+/AX-), and a standard safety signal that generally predicted threat omission (BC-). Both safety signals evoked equivalent autonomic and subjective learning responses but diverged strongly in terms of underlying brain activation (PFDR whole-brain corrected). The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular, and dorsolateral PFC compared with the standard safety signal, whereas the latter evoked greater activation of the ventromedial PFC, posterior cingulate, and hippocampus, among other regions. Further analyses of the conditioned inhibitor indicated that its initial learning was characterized by consistent engagement of dorsal striatal, midbrain, thalamic, premotor, and prefrontal subregions. These findings suggest that safety learning via conditioned inhibition involves a distributed cortico-striatal circuitry, separable from broader cortical regions involved with processing standard safety signals (e.g., CS-). This cortico-striatal system could represent a novel neural substrate of safety learning, underlying the initial generation of "stimulus-safety" associations, distinct from wider cortical correlates of safety processing, which facilitate the behavioral outcomes of learning.SIGNIFICANCE STATEMENT Identifying safety is critical for maintaining adaptive levels of anxiety, but the neural mechanisms of human safety learning remain unclear. Using 7 Tesla fMRI, we compared learning-related brain activity for a conditioned inhibitor, which actively predicted threat omission, and a standard safety signal (CS-), which was passively unpaired with threat. The inhibitor engaged an extended circuitry primarily featuring the dorsal striatum, along with thalamic, midbrain, and premotor/PFC regions. The CS- exclusively involved cortical safety-related regions observed in basic safety conditioning, such as the vmPFC. These findings extend current models to include learning-specific mechanisms for encoding stimulus-safety associations, which might be distinguished from expression-related cortical mechanisms. These insights may suggest novel avenues for targeting dysfunctional safety learning in psychopathology.

Safety learning and the Pavlovian conditioned inhibition of fear in humans: Current state and future directions.

Safety learning occurs when an otherwise neutral stimulus comes to signal the absence of threat, allowing organisms to use safety information to inhibit fear and anxiety in nonthreatening environments. Although it continues to emerge as a topic of relevance in biological and clinical psychology, safety learning remains inconsistently defined and under-researched. Here, we analyse the Pavlovian conditioned inhibition paradigm and its application to the study of safety learning in humans. We discuss existing studies; address outstanding theoretical considerations; and identify prospects for its further application. Though Pavlovian conditioned inhibition presents a theoretically sound model of safety learning, it has been investigated infrequently, with decade-long interims between some studies, and notable methodological variability. Consequently, we argue that the full potential of conditioned inhibition as a model for human safety learning remains untapped, and propose that it could be revisited as a framework for addressing timely questions in the behavioural and clinical sciences.

Characterizing human safety learning via Pavlovian conditioned inhibition.

Deficient safety learning has been implicated in the pathogenesis of anxiety disorders. Despite increased translational interest, there has been limited research on the basis of safety learning in humans. Here, we examined safety learning in seventy-three healthy participants via a modified Pavlovian conditioned inhibition paradigm, featuring a conditioned threat stimulus that was reinforced alone (A+), but not when combined with a second stimulus (the conditioned inhibitor, AX-). During a test phase, X and a control safety cue (C) were combined with a second threat stimulus to assess their inhibition of threat responses, measured via skin conductance (SCRs) and US-expectancy ratings. Both stimuli exhibited conditioned inhibition, but X suppressed ratings by a greater magnitude than C. Trait anxiety also predicted increased US-expectancy ratings of X. These findings suggest that a Pavlovian inhibitor accrues greater safety value than a merely unreinforced safety signal. Conditioned inhibition paradigms may have utility in the ongoing study of safety learning and its relevance to anxious psychopathology.

Dopamine, endocannabinoids and their interaction in fear extinction and negative affect in PTSD.

There currently exist few frameworks for common neurobiology between reexperiencing and negative cognitions and mood symptoms of PTSD. Adopting a dopaminergic framework for PTSD unites many aspects of unique symptom clusters, and this approach also links PTSD symptomology to common comorbidities with a common neurobiological deficiency. Here we review the dopamine literature and incorporate it with a growing field of research that describes both the contribution of endocannabinoids to fear extinction and PTSD, as well as the interactions between dopaminergic and endocannabinoid systems underlying this disorder. Based on current evidence, we outline an early, preliminary model that links re-experiencing and negative cognitions and mood in PTSD by invoking the interaction between endocannabinoid and dopaminergic signalling in the brain. These interactions between PTSD, dopamine and endocannabinoids may have implications for future therapies for treatment-resistant and comorbid PTSD patients.

Inconsistent analytic strategies reduce robustness in fear extinction via skin conductance response.

Robustness of fear conditioning and extinction paradigms has become increasingly important for many researchers interested in improving the study of anxiety and trauma disorders. We recently illustrated the wide variability in data analysis techniques in this paradigm, which we argued may result in a lack of robustness. In the current study, we resampled data from six of our own fear acquisition and extinction data sets, with skin conductance as the outcome. In the resampled and original data sets, we found that effect sizes that were calculated using discrepant statistical strategies, sourced from a non-exhaustive search of high-impact articles, were often poorly correlated. The main contributors to poor correlations were the selection of trials from different stages of each experimental phase and the use of average compared to trial-by-trial analysis. These findings reinforce the importance of focusing on robustness in the psychophysiological measurement of fear acquisition and extinction in the laboratory and may guide prospective researchers in which decisions may most impact the robustness of their results.

Individual differences in anxiety and fear learning: The role of working memory capacity.

Anxiety disorders are characterised by the perception of fear and threat in the presence of stimuli that are neutral or ambiguous. Attempts in previous research to explain the relationship between anxiety and fear learning have been inconsistent, possibly due to the influence of an unmeasured mechanism that mediates the relationship between them. Working memory capacity has been suggested as one such mechanism. The current study investigated the influence of anxiety-based individual differences upon associative fear learning, while accounting for individual differences in working memory. We hypothesised that individuals high in both anxiety and working memory would show unimpaired fear learning whereas individuals high in anxiety and low in working memory would exhibit dysfunctional fear learning. Sixty participants completed a battery of anxiety and working memory tests, as well as a fear conditioning experiment that tested for blocking, conditioned inhibition and fear discrimination. We found that anxious individuals were more likely to show impaired fear discrimination only if they also had a low working memory capacity. Furthermore, anxiety was particularly associated with poorer learning about safety cues. Such relationships were not observed for blocking and conditioned inhibition. These results suggest that the relationship between anxiety and fear learning is complex and warrants further investigation of the potential mediating role of higher-order cognitive faculties.

Filling the Void: A Review of Intragastric Balloons for Obesity.

Endoscopic bariatric therapies are predicted to become much more widely used in North America for obese patients who are not candidates for bariatric surgery. Of all the endoscopic bariatric therapies, intragastric balloons (IGBs) have the greatest amount of clinical experience and published data supporting their use. Three IGBs are FDA approved and are now commercially available in the USA (Orbera, ReShape Duo, and Obalon) with others likely soon to follow. They are generally indicated for patients whose BMI ranges from 30 to 40 mg/kg2 and who have failed to lose weight with diet and exercise. IGBs have been shown to be safe, effective, and relatively straightforward to place and remove. Accommodative symptoms commonly occur within the initial weeks post-placement; however, major complications are rare. Gastric ulceration can occur in up to 10% of patients, while balloon deflation with migration and bowel obstruction occurs in <1% of patients. The effectiveness of the Orbera and ReShape Duo IGBs ranges from 25 to 50% EWL (excess weight loss) after 6 months of therapy. The use of IGBs is likely to grow dramatically in the USA, and gastroenterologists and endoscopists should be familiar with their indications/contraindications, efficacy, placement/removal, and complications.

A new "tension side" locking plate for Hallux Valgus: A prospective multicentre case series.

BACKGROUND: Proximal osteotomy of the first metatarsal is often indicated for Hallux Valgus correction. Previously recognised complications however, include transfer metatarsalgia, first metatarsophalangeal joint stiffness, problems with fixation and prominence of metalware. METHODS: We report on one year follow up of an international prospective series between June 2009 and October 2012 involving three centres, including 91 feet (58 patients) that underwent proximal osteotomy, using a new locking plate applied to the plantar surface of the metatarsal. RESULTS: Mean Hallux Valgus angle improved from 27.9 (±13.1)° to 12.4 (±8.2)° while mean Intermetatarsal angle improved from 12.5 (±8.4) to 7.1 (±3.4) and there was a statistically significant improvement in both mean AOFAS-HMI score 54.2 (±13.9) to 94.0 (±9.5) and Visual Analogue Pain Scale 4.7 (±1.5) to 0.6 (±1.3). 70% of patients were back at their preoperative employment at five weeks. Mean surgical time was 56min and the plate was generally well tolerated. There were five implant related complications. CONCLUSIONS: Locked fixation from the tension side of the construct encourages early weight bearing with a low risk of implant prominence. Our radiological, functional and clinical parameters are comparable with similar series and we therefore recommend this technique.

Stage of hilar cholangiocarcinoma predicts recurrence of biliary obstruction in patients with metal stents.

BACKGROUND & AIMS: Most patients with hilar cholangiocarcinomas present with unresectable tumors, so only palliative biliary drainage with self-expanding metal stents (SEMS) is possible. Stents eventually cease to function because of tumor overgrowth and/or other causes, so it is important to identify factors that affect stent patency and failure. We examined the patency of endoscopically placed SEMS in patients with hilar cholangiocarcinoma and factors associated with patency. METHODS: We performed a retrospective study of 120 consecutive patients (mean age, 67 ± 14.6 years; 74 male) who presented with obstructive jaundice from hilar cholangiocarcinoma and underwent bilateral SEMS from September 2006 through April 2012 at 2 US tertiary medical centers. We collected data on patient demographics and survival, success of stent placement and function, and immediate adverse events. The primary outcome was duration of stent patency (time from insertion to failure). RESULTS: Thirty-eight patients had stage 1 hilar cholangiocarcinomas, 45 had stage 2, 12 had stage 3, and 25 had stage 4. The median length of the hilar stricture was 9 mm (range, 8-50 mm). The stent was successfully passaged across the stricture in all patients and was functional in 115; its median length was 8 mm (range, 8-10 mm), and diameter was 80 mm (range, 60-100 mm). Fourteen patients had immediate adverse events, including perforation (n = 2), bleeding (n = 2), pancreatitis (n = 9), and cholangitis (n = 1). Median survival was 17 weeks (range, 1-211 weeks), and 50 patients had stent occlusion. On Kaplan-Meier analysis, the median time from stent placement to occlusion was 17 weeks (range, 1-104 weeks). More patients with stage 3 or 4 tumors (64%) had SEMS occlusion than patients with stage 1 or 2 tumors (28%) in univariate analysis (P = .017). In multivariate analysis, only cancer stage was independently and significantly associated with patency (P = .006; hazard ratio, 2.77); age, sex, length of stricture, and SEMS diameter and length were not. CONCLUSIONS: The cumulative patency of bilateral SEMS for hilar cholangiocarcinoma significantly decreases as tumor stage increases. Age, sex, length of stricture, and SEMS diameter and length are not associated with SEMS patency.

Cell cultured chondrocyte implantation and scaffold techniques for osteochondral talar lesions.

Cell cultured techniques have gained interest and popularity in osteochondral defects because, unlike bone marrow stimulation methods, where fibrocartilage fills the defect, they allow for the regeneration of "hyaline-like cartilage" with better stiffness, resilience, and wear characteristics. Osteochondral defects in the ankle are a rare but challenging problem to treat in young active patients. If left alone, they can cause pain and reduced function and risk progressive degenerative changes in the joint. Clinical results of cell cultured and scaffold technology in the ankle, although still limited by small studies and midterm follow-up, are certainly encouraging.

Distribution patterns of zoochlorellae and zooxanthellae hosted by two Pacific Northeast anemones, Anthopleura elegantissima and A. xanthogrammica.

This study investigated patterns in the relative abundance of two photosynthetic algal symbionts, zoochlorellae (ZC) and zooxanthellae (ZX), hosted by two temperate anemones, Anthopleura elegantissima and A. xanthogrammica. Previous studies have documented varying proportions of each symbiont along environmental gradients, presumably determined by their respective physiological capabilities. To test for differences in the algal type between the two host species, we sampled anemone tissues (tentacle or tentacle and body column) of similarly sized polyps that were located close together in multiple habitats: tidepools, crevices, underneath rock ledges, and along natural light gradients in caves. The ZC-A. elegantissima symbiosis was rare on the west coast of Vancouver Island, British Columbia, Canada. Even in low-irradiance habitats, ZC were the dominant algae hosted by A. xanthogrammica, while nearby A. elegantissima hosted ZX or was algae-free. As a first step in determining whether symbiont growth rates differed between the two host species, we quantified mitotic index (MI), the percentage of cells with division furrows, under artificial light and in the field by simultaneously sampling tentacles from both species. MI was more stable in A. elegantissima: the MI of ZX isolated from the tentacles of A. xanthogrammica was slightly higher at a light level of 80 micromol quanta m(-2) s(-1) than it was for ZX from A. elegantissima (respectively, 7.3 vs. 6.2) and relatively lower at 40 micromol quanta m(-2) s(-1) (3.9 vs. 5.6). Our data indicate host-specific differences in symbiont distributions and MI when extrinsic physical parameters were similar.

The effect of newer anti-rheumatic drugs on osteogenic cell proliferation: an in-vitro study.

BACKGROUND: Disease modifying anti-rheumatic drugs (DMARDs) may interfere with bone healing. Previous studies give conflicting advice regarding discontinuation of these drugs in the peri-operative setting. No consensus exists in current practice especially with the newer DMARDs such as Leflunomide, Etanercept, and Infliximab. The aim of this study was to assess the in-vitro effect of these drugs alone and in relevant clinical combinations on Osteoblast activity. METHODS: Osteoblasts were cultured from femoral heads obtained from five young otherwise healthy patients undergoing total hip replacement. The cells were cultured using techniques that have been previously described. A full factorial design was used to set up the experiment on samples obtained from the five donors. Normal therapeutic concentrations of the various DMARDs were added alone and in combination to the media. The cell proliferation was estimated after two weeks using spectrophotometric technique using Roche Cell proliferation Kit. Multilevel regression analysis was used to estimate which drugs or combination of drugs significantly affected cell proliferation. RESULTS: Infliximab and Leflunomide had an overall significant inhibitory effect (p < 0.05). Dexamethasone had a small stimulatory effect that was however strongly donor-dependent. The cox-2 inhibitor Etoricoxib was found to negate or increase the action of two other drugs (Leflunomide and Dexamethasone). Methotrexate and Etanercept had no discernable donor-dependant or donor-independent effect on osteoblast proliferation. CONCLUSION: Our study indicates that in-vitro osteoblast proliferation can be inhibited by the presence of certain DMARDs. Combinations of drugs had an influence and could negate the action of a drug on osteoblast proliferation. The response to drugs may be donor-dependent.

Correlation of the AOFAS scores with a generic health QUALY score in foot and ankle surgery.

BACKGROUND: The American Orthopaedic Foot and Ankle Score (AOFAS) is one scoring system used to assess and monitor the progress of patients after foot and ankle surgery. The aim of this study was to evaluate the trend of the AOFAS score over a period of time and correlate it with the QUALY score, which is a valid and reliable scoring system. METHODS: All patients undergoing surgery by one foot and ankle surgeon between January, 2001, and July, 2003, were reviewed. The preoperative AOFAS and QUALY and postoperative scores at 3, 6 and 12 months, and yearly were collected prospectively. RESULTS: This study includes 204 operative procedures in 159 patients. The mean age of the patients was 51.9 (range 12 to 89) years. The AOFAS scores increased from a mean of 45.5 preoperatively to 76.5 at 3 months and reached a peak of 81.5 at 6 months and then started to decrease to 79.2 at 12 months. This fall, though seemingly marginal, was significant (p < 0. 01). This trend seems to be consistent for all the procedures. The 6-month AOFAS score was found to have a higher correlation with the final QUALY score (r(2) = 0.423) than the 12-month AOFAS score (r(2) = 0.326). CONCLUSIONS: The AOFAS score has low levels of correlation with the validated generic health QUALY score. Our study suggests that scores collected preoperatively, at 6 and 12 months after surgery, and annually there after may be best. The 3-month score may not be necessary. We recommend that a generic health score such as the QUALY score be used in conjunction with the AOFAS score to reflect outcome.

Iatrogenic blunt arterial injury during a hip fracture surgery.

Iatrogenic non-penetrating arterial injuries have been reported following primary and revision hip arthroplasties. We report a patient who developed acute limb ischaemia after dynamic hip screw fixation was performed for an unstable intertrochanteric fracture. We discuss a previously unreported mechanism of traction creating tension on the atherosclerosed vessels and medial retraction tenting and breaking the vessel wall lining. This case highlights a serious complication in one of the most commonly performed hip surgeries.