Propensity for risky choices despite lower cue reactivity in adolescent rats.

Adolescence is a time of heightened risk-taking across species. Salient audiovisual cues associated with rewards are a common feature of gambling environments and have been connected to increased risky decision-making. We have previously shown that, in adult male rats, sign tracking - a behavioral measure of cue reactivity - predicts an individual's propensity for suboptimal risky choices in a rodent gambling task (rGT) with win-paired cues. However, adolescents perform less sign tracking than adult animals, suggesting that they are less cue-reactive than adults in some circumstances. Therefore, we investigated the performance of adolescent male rats on the rGT with win cues and examined its relationship with their sign-tracking behavior. We found that adolescents make more risky choices and fewer optimal choices on the rGT compared with adults, evidence of the validity of the rGT as a model of adolescent gambling behavior. We also confirmed that adolescents perform less sign tracking than adults, and we found that, unlike in adults, adolescents' sign tracking was unrelated to their risk-taking in the rGT. This implies that adolescent risk-taking is less likely than that of adults to be driven by reward-related cues. Finally, we found that adults trained on the rGT as adolescents retained an adolescent-like propensity toward risky choices, suggesting that early exposure to a gambling environment may have a long-lasting impact on risk-taking behavior.

Excitatory and Inhibitory Signaling in the Nucleus Accumbens Encode Different Aspects of a Pavlovian Cue in Sign Tracking and Goal Tracking Rats.

When a Pavlovian cue is presented separately from its associated reward, some animals will acquire a sign tracking (ST) response - approach and/or interaction with the cue - while others will acquire a goal tracking response - approach to the site of reward. We have previously shown that cue-evoked excitations in the nucleus accumbens (NAc) encode the vigor of both behaviors; in contrast, reward-related responses diverge over the course of training, possibly reflecting neurochemical differences between sign tracker and goal tracker individuals. However, a substantial subset of neurons in the NAc exhibit inhibitory, rather than excitatory, cue-evoked responses, and the evolution of their signaling during Pavlovian conditioning remains unknown. Using single-neuron recordings in behaving rats, we show that NAc neurons with cue-evoked inhibitions have distinct coding properties from neurons with cue-evoked excitations. Cue-evoked inhibitions become more numerous over the course of training and, like excitations, may encode the vigor of sign tracking and goal tracking behavior. However, the responses of cue-inhibited neurons do not evolve differently between sign tracker and goal tracker individuals. Moreover, cue-evoked inhibitions, unlike excitations, are insensitive to extinction of the cue-reward relationship. Finally, we show that cue-evoked excitations are greatly diminished by reward devaluation, while inhibitory cue responses are virtually unaffected. Overall, these findings converge with existing evidence that cue-excited neurons in NAc, but not cue-inhibited neurons, are profoundly sensitive to the same behavior variations that are often associated with changes in dopamine release.

Sign tracking predicts suboptimal behavior in a rodent gambling task.

RATIONALE: Reward-associated cues can promote maladaptive behavior, including risky decision-making in a gambling setting. A propensity for sign tracking over goal tracking-i.e., interaction with a reward-predictive cue rather than the site of reward-demonstrates an individual's tendency to transfer motivational value to a cue. However, the relationship of sign tracking to risky decision-making remains unclear. OBJECTIVES: To determine whether sign tracking predicts risky choice, we used a Pavlovian conditioned approach task to evaluate the tendency of male rats to sign track to a lever cue and then trained rats on a rodent gambling task (rGT) with win-associated cues. We also tested the effects of D-amphetamine, quinpirole (a D2/D3 receptor agonist), and PD128907 (a D3 receptor agonist) on gambling behavior in sign tracker and goal tracker individuals. RESULTS: Increased sign tracking relative to goal tracking was associated with suboptimal performance on the rGT, including decreased selection of the optimal choice, increased selection of a high-risk/high-reward option, and increased impulsive premature choices. Amphetamine increased choices of a low-risk/low-reward option at the expense of optimal and high-risk choices, whereas quinpirole and PD128907 had little effect on choice allocation, but reduced impulsivity. Drug effects were similar across sign tracker and goal tracker individuals. CONCLUSIONS: Cue reactivity, as measured by sign tracking, is predictive and may be an important driver of risky and impulsive choices in a gambling setting laden with salient audiovisual cues. Evaluating an individual's sign tracking behavior may be an avenue to predict vulnerability to pathological gambling and the efficacy of treatments.

Robotic ventral hernia repair in octogenarians: perioperative and long-term outcomes.

Very few studies have documented perioperative outcomes of ventral hernia repair in octogenarians. The aim of this study is to report the perioperative and the long-term outcomes of robotic ventral hernia repair (RVHR) in aged 80-89 years patients. From a prospectively maintained database, aged 80-89 years patients who underwent robotic procedures between 2013 and 2018 were analyzed retrospectively including perioperative outcomes and long-term follow-up. Complications were assessed with validated grading systems and index. 21 octogenarians with average age 83.48 were included. Intraperitoneal onlay mesh repair, transabdominal preperitoneal repair, retromuscular repair with or without transversus abdominis release technique were performed without conversion. The average operating time was 150 min. The mean hospital length of stay of all cohorts was 1.24 day. There was a strong correlation between operating time and hospital length of stay. The median follow-up was 23.5 months. According to Clavien-Dindo classification, grade-I and grade-II complications were observed in 23.8% and 28.6% patients, respectively; major complications (grade-III and IV) were not observed. The maximum Comprehensive Complication Index® score was 29.6. None of the patients experienced hernia recurrence or chronic pain. To our best knowledge this study is the first to present perioperative as well as long-term outcomes of octogenarian patients who underwent RVHR. The results indicate the safety and efficacy of RVHR in octogenarians.

Robotic ventral hernia repair in morbidly obese patients: perioperative and mid-term outcomes.

BACKGROUND: Obesity is a growing epidemic and it has been found to be an independent risk factor for a multitude of perioperative complications. We describe our experience with morbidly obese patients who underwent robotic ventral hernia repair (RVHR), examining factors affecting perioperative and mid-term outcomes. METHODS: From a prospectively maintained database, all morbid obese (BMI ≥ 40 kg/m2) patients who underwent robotic procedures between 2013 and 2018 were analyzed retrospectively including perioperative outcomes and the mid-term follow-up. Complications were assessed with validated grading systems and index. Univariate analyses and multivariate logistic regression analysis were performed to determine the factors associated with the development of any complication. Kaplan-Meier's time-to-event analysis was performed to calculate freedom-of-recurrence. RESULTS: Fifty patients with median BMI 42.9 kg/m2 were included. The median last pain score before leaving PACU was 4. The mean LOS of all cohorts was 0.32 day. The postoperative complication rate was 46%. The most frequent complication was persistent pain/discomfort (32%) in early postoperative period. Minor complications (Clavien-Dindo grade-I and II) were seen in 40% of patients while major complications (Clavien-Dindo grade-III and IV) were seen in 6%. The maximum comprehensive complication index® score was 42.9. In regression analysis, BMI, adhesiolysis, intraperitoneal mesh placement, and off-console time were found to be significantly associated with postoperative complications. Mean follow-up was 22.7 months. Hernia recurrence was seen in 2% and the mean freedom-of-recurrence was 57.4 months (95% CI 54.6-60.2). CONCLUSIONS: To our best knowledge, this study is the first to present outcomes of morbidly obese patients who underwent RVHR. The results indicate the safety and efficacy of RVHR in morbid obesity with a low recurrence rate as well as a long freedom-of-recurrence time. Further studies are needed to better elucidate the role of robotic surgery in morbidly obese patients.

Sign Tracking and Goal Tracking Are Characterized by Distinct Patterns of Nucleus Accumbens Activity.

During Pavlovian conditioning, if a cue (e.g., lever extension) predicts reward delivery in a different location (e.g., a food magazine), some individuals will come to approach and interact with the cue, a behavior known as sign tracking (ST), and others will approach the site of reward, a behavior known as goal tracking (GT). In rats, the acquisition of ST versus GT behavior is associated with distinct profiles of dopamine release in the nucleus accumbens (NAc), but it is unknown whether it is associated with different patterns of accumbens neural activity. Therefore, we recorded from individual neurons in the NAc core during the acquisition, maintenance, and extinction of ST and GT behavior. Even though NAc dopamine is specifically important for the acquisition and expression of ST, we found that cue-evoked excitatory responses encode the vigor of both ST and GT behavior. In contrast, among sign trackers only, there was a prominent decrease in reward-related activity over the course of training, which may reflect the decreasing reward prediction error encoded by phasic dopamine. Finally, both behavior and cue-evoked activity were relatively resistant to extinction in sign trackers, as compared with goal trackers, although a subset of neurons in both groups retained their cue-evoked responses. Overall, the results point to the convergence of multiple forms of reward learning in the NAc.

Increased Goal Tracking in Adolescent Rats Is Goal-Directed and Not Habit-Like.

When a cue is paired with reward in a different location, some animals will approach the site of reward during the cue, a behavior called goal tracking, while other animals will approach and interact with the cue itself: a behavior called sign tracking. Sign tracking is thought to reflect a tendency to transfer incentive salience from the reward to the cue. Adolescence is a time of heightened sensitivity to rewards, including environmental cues that have been associated with rewards, which may account for increased impulsivity and vulnerability to drug abuse. Surprisingly, however, studies have shown that adolescents are actually less likely to interact with the cue (i.e., sign track) than adult animals. We reasoned that adolescents might show decreased sign tracking, accompanied by increased apparent goal tracking, because they tend to attribute incentive salience to a more reward-proximal "cue": the food magazine. On the other hand, adolescence is also a time of enhanced exploratory behavior, novelty-seeking, and behavioral flexibility. Therefore, adolescents might truly express more goal-directed reward-seeking and less inflexible habit-like approach to a reward-associated cue. Using a reward devaluation procedure to distinguish between these two hypotheses, we found that adolescents indeed exhibit more goal tracking, and less sign tracking, than a comparable group of adults. Moreover, adolescents' goal tracking behavior is highly sensitive to reward devaluation and therefore goal-directed and not habit-like.

Maintenance of macrophage transcriptional programs and intestinal homeostasis by epigenetic reader SP140.

Epigenetic "readers" that recognize defined posttranslational modifications on histones have become desirable therapeutic targets for cancer and inflammation. SP140 is one such bromodomain- and plant homeodomain (PHD)-containing reader with immune-restricted expression, and single-nucleotide polymorphisms (SNPs) within SP140 associate with Crohn's disease (CD). However, the function of SP140 and the consequences of disease-associated SP140 SNPs have remained unclear. We show that SP140 is critical for transcriptional programs that uphold the macrophage state. SP140 preferentially occupies promoters of silenced, lineage-inappropriate genes bearing the histone modification H3K27me3, such as the HOXA cluster in human macrophages, and ensures their repression. Depletion of SP140 in mouse or human macrophages resulted in severely compromised microbe-induced activation. We reveal that peripheral blood mononuclear cells (PBMCs) or B cells from individuals carrying CD-associated SNPs within SP140 have defective SP140 messenger RNA splicing and diminished SP140 protein levels. Moreover, CD patients carrying SP140 SNPs displayed suppressed innate immune gene signatures in a mixed population of PBMCs that stratified them from other CD patients. Hematopoietic-specific knockdown of Sp140 in mice resulted in exacerbated dextran sulfate sodium (DSS)-induced colitis, and low SP140 levels in human CD intestinal biopsies correlated with relatively lower intestinal innate cytokine levels and improved response to anti-tumor necrosis factor (TNF) therapy. Thus, the epigenetic reader SP140 is a key regulator of macrophage transcriptional programs for cellular state, and a loss of SP140 due to genetic variation contributes to a molecularly defined subset of CD characterized by ineffective innate immunity, normally critical for intestinal homeostasis.

Limbic-motor integration by neural excitations and inhibitions in the nucleus accumbens.

The nucleus accumbens (NAc) has often been described as a "limbic-motor interface," implying that the NAc integrates the value of expected rewards with the motor planning required to obtain them. However, there is little direct evidence that the signaling of individual NAc neurons combines information about predicted reward and behavioral response. We report that cue-evoked neural responses in the NAc form a likely physiological substrate for its limbic-motor integration function. Across task contexts, individual NAc neurons in behaving rats robustly encode the reward-predictive qualities of a cue, as well as the probability of behavioral response to the cue, as coexisting components of the neural signal. In addition, cue-evoked activity encodes spatial and locomotor aspects of the behavioral response, including proximity to a reward-associated target and the latency and speed of approach to the target. Notably, there are important limits to the ability of NAc neurons to integrate motivational information into behavior: in particular, updating of predicted reward value appears to occur on a relatively long timescale, since NAc neurons fail to discriminate between cues with reward associations that change frequently. Overall, these findings suggest that NAc cue-evoked signals, including inhibition of firing (as noted here for the first time), provide a mechanism for linking reward prediction and other motivationally relevant factors, such as spatial proximity, to the probability and vigor of a reward-seeking behavioral response.NEW & NOTEWORTHY The nucleus accumbens (NAc) is thought to link expected rewards and action planning, but evidence for this idea remains sparse. We show that, across contexts, both excitatory and inhibitory cue-evoked activity in the NAc jointly encode reward prediction and probability of behavioral responding to the cue, as well as spatial and locomotor properties of the response. Interestingly, although spatial information in the NAc is updated quickly, fine-grained updating of reward value occurs over a longer timescale.

Intestinal Alkaline Phosphatase Attenuates Alcohol-Induced Hepatosteatosis in Mice.

BACKGROUND AND AIMS: Bacterially derived factors from the gut play a major role in the activation of inflammatory pathways in the liver and in the pathogenesis of alcoholic liver disease. The intestinal brush-border enzyme intestinal alkaline phosphatase (IAP) detoxifies a variety of bacterial pro-inflammatory factors and also functions to preserve gut barrier function. The aim of this study was to investigate whether oral IAP supplementation could protect against alcohol-induced liver disease. METHODS: Mice underwent acute binge or chronic ethanol exposure to induce alcoholic liver injury and steatosis ± IAP supplementation. Liver tissue was assessed for biochemical, inflammatory, and histopathological changes. An ex vivo co-culture system was used to examine the effects of alcohol and IAP treatment in regard to the activation of hepatic stellate cells and their role in the development of alcoholic liver disease. RESULTS: Pretreatment with IAP resulted in significantly lower serum alanine aminotransferase compared to the ethanol alone group in the acute binge model. IAP treatment attenuated the development of alcohol-induced fatty liver, lowered hepatic pro-inflammatory cytokine and serum LPS levels, and prevented alcohol-induced gut barrier dysfunction. Finally, IAP ameliorated the activation of hepatic stellate cells and prevented their lipogenic effect on hepatocytes. CONCLUSIONS: IAP treatment protected mice from alcohol-induced hepatotoxicity and steatosis. Oral IAP supplementation could represent a novel therapy to prevent alcoholic-related liver disease in humans.

Intestinal alkaline phosphatase decreases intraperitoneal adhesion formation.

BACKGROUND: Damage to the peritoneum initiates an inflammatory response leading to the formation of adhesions, which subsequently cause significant morbidity in some patients. Intestinal alkaline phosphatase (IAP) is a gut enzyme capable of detoxifying various inflammatory mediators such as lipopolysaccharide, lipoteichoic acid, CpG DNA, and adenosine triphosphate. In this study, we aimed to examine the anti-inflammatory effects of IAP on postoperative adhesions in mice. METHODS: C57BL/6 mice were subjected to a midline laparotomy and then six musculoperitoneal buttons (MPBs) were created by pinching and ligating the peritoneum and underlying muscle. The buttons were half-excised and E-cauterized, and then cecal abrasion was performed. Five hundred microliters of vehicle with IAP 5000 U or vehicle alone were applied over the peritoneal cavity. In some experiments, the mice were euthanized on the first and second postoperative day (POD), and cytokines analysis was done on the MPB, peritoneal tissue, and peritoneal fluid. In separate experiments, the mice were sacrificed on the 21st POD, and adhesion to each button was scored based on type and tenacity. RESULTS: IAP group mice had significantly lower adhesion scores compared with controls (21.5 ± 1.7 versus 13.2 ± 1.3; P = 0.0014, n = 15). MPB from IAP group mice had significantly lower interleukin-1ß and tumor necrosis factor-α protein level compared to control mice (105.66 ± 4.5 versus 69.8 ± 4.8 versus pg/mg, P = 0.0001; 45.25 ± 2.8 pg/mg versus 24.88 ± 4.1 pg/mg; P = 0.0007, n = 10). IAP treatment significantly decreased interleukin-1ß and tumor necrosis factor-α mRNA expression in MPB in the first POD (1.14 ± 0.25 versus 0.33 ± 0.07; P = 0.0068; 1.33 ± 0.31 versus 0.33 ± 0.08; P = 0.0064, n = 10). CONCLUSIONS: Application of IAP during laparotomy could represent a novel approach to prevent postoperative adhesions.

Inhibition of the gut enzyme intestinal alkaline phosphatase may explain how aspartame promotes glucose intolerance and obesity in mice.

Diet soda consumption has not been associated with tangible weight loss. Aspartame (ASP) commonly substitutes sugar and one of its breakdown products is phenylalanine (PHE), a known inhibitor of intestinal alkaline phosphatase (IAP), a gut enzyme shown to prevent metabolic syndrome in mice. We hypothesized that ASP consumption might contribute to the development of metabolic syndrome based on PHE's inhibition of endogenous IAP. The design of the study was such that for the in vitro model, IAP was added to diet and regular soda, and IAP activity was measured. For the acute model, a closed bowel loop was created in mice. ASP or water was instilled into it and IAP activity was measured. For the chronic model, mice were fed chow or high-fat diet (HFD) with/without ASP in the drinking water for 18 weeks. The results were that for the in vitro study, IAP activity was lower (p < 0.05) in solutions containing ASP compared with controls. For the acute model, endogenous IAP activity was reduced by 50% in the ASP group compared with controls (0.2 ± 0.03 vs 0.4 ± 0.24) (p = 0.02). For the chronic model, mice in the HFD + ASP group gained more weight compared with the HFD + water group (48.1 ± 1.6 vs 42.4 ± 3.1, p = 0.0001). Significant difference in glucose intolerance between the HFD ± ASP groups (53 913 ± 4000.58 (mg·min)/dL vs 42 003.75 ± 5331.61 (mg·min)/dL, respectively, p = 0.02). Fasting glucose and serum tumor necrosis factor-alpha levels were significantly higher in the HFD + ASP group (1.23- and 0.87-fold increases, respectively, p = 0.006 and p = 0.01). In conclusion, endogenous IAP's protective effects in regard to the metabolic syndrome may be inhibited by PHE, a metabolite of ASP, perhaps explaining the lack of expected weight loss and metabolic improvements associated with diet drinks.

Sign Tracking, but Not Goal Tracking, is Resistant to Outcome Devaluation.

During Pavlovian conditioning, a conditioned stimulus (CS) may act as a predictor of a reward to be delivered in another location. Individuals vary widely in their propensity to engage with the CS (sign tracking) or with the site of eventual reward (goal tracking). It is often assumed that sign tracking involves the association of the CS with the motivational value of the reward, resulting in the CS acquiring incentive value independent of the outcome. However, experimental evidence for this assumption is lacking. In order to test the hypothesis that sign tracking behavior does not rely on a neural representation of the outcome, we employed a reward devaluation procedure. We trained rats on a classic Pavlovian paradigm in which a lever CS was paired with a sucrose reward, then devalued the reward by pairing sucrose with illness in the absence of the CS. We found that sign tracking behavior was enhanced, rather than diminished, following reward devaluation; thus, sign tracking is clearly independent of a representation of the outcome. In contrast, goal tracking behavior was decreased by reward devaluation. Furthermore, when we divided rats into those with high propensity to engage with the lever (sign trackers) and low propensity to engage with the lever (goal trackers), we found that nearly all of the effects of devaluation could be attributed to the goal trackers. These results show that sign tracking and goal tracking behavior may be the output of different associative structures in the brain, providing insight into the mechanisms by which reward-associated stimuli-such as drug cues-come to exert control over behavior in some individuals.

Neurons in the nucleus accumbens promote selection bias for nearer objects.

Both animals and humans often prefer rewarding options that are nearby over those that are distant, but the neural mechanisms underlying this bias are unclear. Here we present evidence that a proximity signal encoded by neurons in the nucleus accumbens drives proximate reward bias by promoting impulsive approach to nearby reward-associated objects. On a novel decision-making task, rats chose the nearer option even when it resulted in greater effort expenditure and delay to reward; therefore, proximate reward bias was unlikely to be caused by effort or delay discounting. The activity of individual neurons in the nucleus accumbens did not consistently encode the reward or effort associated with specific alternatives, suggesting that it does not participate in weighing the values of options. In contrast, proximity encoding was consistent and did not depend on the subsequent choice, implying that accumbens activity drives approach to the nearest rewarding option regardless of its specific associated reward size or effort level.

A novel approach to maintain gut mucosal integrity using an oral enzyme supplement.

OBJECTIVE: To determine the role of intestinal alkaline phosphatase (IAP) in enteral starvation-induced gut barrier dysfunction and to study its therapeutic effect as a supplement to prevent gut-derived sepsis. BACKGROUND: Critically ill patients are at increased risk for systemic sepsis and, in some cases, multiorgan failure leading to death. Years ago, the gut was identified as a major source for this systemic sepsis syndrome. Previously, we have shown that IAP detoxifies bacterial toxins, prevents endotoxemia, and preserves intestinal microbiotal homeostasis. METHODS: WT and IAP-KO mice were used to examine gut barrier function and tight junction protein levels during 48-hour starvation and fed states. Human ileal fluid samples were collected from 20 patients postileostomy and IAP levels were compared between fasted and fed states. To study the effect of IAP supplementation on starvation-induced gut barrier dysfunction, WT mice were fasted for 48 hours +/- IAP supplementation in the drinking water. RESULTS: The loss of IAP expression is associated with decreased expression of intestinal junctional proteins and impaired barrier function. For the first time, we demonstrate that IAP expression is also decreased in humans who are deprived of enteral feeding. Finally, our data demonstrate that IAP supplementation reverses the gut barrier dysfunction and tight junction protein losses due to a lack of enteral feeding. CONCLUSIONS: IAP is a major regulator of gut mucosal permeability and is able to ameliorate starvation-induced gut barrier dysfunction. Enteral IAP supplementation may represent a novel approach to maintain bowel integrity in critically ill patients.

Efficacy and safety of continuous low-irradiance photodynamic therapy in the treatment of chest wall progression of breast cancer.

BACKGROUND: Photodynamic therapy (PDT) is a binary therapy using a drug and high-energy light source. PDT is approved for several premalignant and malignant conditions. Recent in-vitro and animal data suggest that enhanced tumor-specific cytotoxicity can be achieved with far less collateral damage to normal surrounding tissues if PDT is administered continuously at a lower dose rate for extended periods of time. Based on these promising preclinical data, we conducted a Phase I clinical trial of continuous low-irradiance photodynamic therapy (CLIPT) using 630 nm laser energy and intravenously administered porforin sodium as the photosensitizer. We determined the maximum tolerated dose (MTD) of CLIPT on skin and tumor response in subjects with cutaneous and subcutaneous metastatic nodules who had failed radiation and surgery. METHODS: Patients with cutaneous and/or subcutaneous metastatic nodules that had failed radiation and surgery were offered enrollment into the trial. The initial study design planned for sequential cohorts of six subjects to be treated at increasing laser intensity, starting at 100 J/cm(2) administered continuously over 24 h (10(-2) dose rate compared with standard PDT). Dose-limiting toxicity was defined as partial or full-thickness necrosis of the surrounding tumor-free, previously irradiated skin. The MTD was defined as the highest laser energy at which ≤33% of subjects experienced the dose-limiting toxicity. Subjects received intravenous porfirmer sodium 0.8 mg/kg 48 h before commencing CLIPT. Response rates and quality of life measures were assessed. RESULTS: Nine subjects were enrolled with chest wall progression of breast cancer following mastectomy. All had failed prior surgery and electron-beam radiation therapy. The initial two subjects were treated at 100 J/cm(2) and developed partial thickness skin necrosis. Dose reduction was therefore instituted, and the next cohort was treated at 50 J/cm(2). None of the subsequent seven subjects suffered partial or full thickness necrosis, thus establishing the MTD at 50 J/cm(2) over 24 h (0.5 mW irradiance). Six of the nine subjects (67%) had either a complete or partial clinical response. Of note, two subjects had significant regression of tumor nodules distant from the treatment field. Of the eight subjects whose terminal deoxynucleotidyl transferase dUTP nick end labeling assay results were available, 8 (100%) demonstrated histologic response to treatment as evidenced by either tumor apoptosis or regression. Quality of life measures were improved following treatment-particularly bleeding and pain from the tumor nodules. CONCLUSIONS: The MTD of CLIPT was established at 50 J/cm(2) administered continuously over 24 h. These preliminary data suggest CLIPT may be an effective, low-morbidity therapeutic modality in the treatment of cutaneous and subcutaneous metastases of breast cancer following mastectomy. Further evaluation in a larger cohort is warranted to better assess efficacy and optimize the intervention.

The surgical management of thyroid cancer.

Thyroid cancer has been increasing in incidence, with the number of reported cases in the US rising by 25% over the last 3 years. With growing technological advances in the field and improved contributions of diagnostics, surgical decision-making and operative planning have taken on new challenges. Herein, we review the current clinical practice recommendations and active areas of surgical controversy, reflective of the most recently published professional consensus guidelines and a systematic review of the literature.

Functional circuits and anatomical distribution of response properties in the primate amygdala.

Recent electrophysiological studies on the primate amygdala have advanced our understanding of how individual neurons encode information relevant to emotional processes, but it remains unclear how these neurons are functionally and anatomically organized. To address this, we analyzed cross-correlograms of amygdala spike trains recorded during a task in which monkeys learned to associate novel images with rewarding and aversive outcomes. Using this task, we have recently described two populations of amygdala neurons: one that responds more strongly to images predicting reward (positive value-coding), and another that responds more strongly to images predicting an aversive stimulus (negative value-coding). Here, we report that these neural populations are organized into distinct, but anatomically intermingled, appetitive and aversive functional circuits, which are dynamically modulated as animals used the images to predict outcomes. Furthermore, we report that responses to sensory stimuli are prevalent in the lateral amygdala, and are also prevalent in the medial amygdala for sensory stimuli that are emotionally significant. The circuits identified here could potentially mediate valence-specific emotional behaviors thought to involve the amygdala.

Complexity and competition in appetitive and aversive neural circuits.

Decision-making often involves using sensory cues to predict possible rewarding or punishing reinforcement outcomes before selecting a course of action. Recent work has revealed complexity in how the brain learns to predict rewards and punishments. Analysis of neural signaling during and after learning in the amygdala and orbitofrontal cortex, two brain areas that process appetitive and aversive stimuli, reveals a dynamic relationship between appetitive and aversive circuits. Specifically, the relationship between signaling in appetitive and aversive circuits in these areas shifts as a function of learning. Furthermore, although appetitive and aversive circuits may often drive opposite behaviors - approaching or avoiding reinforcement depending upon its valence - these circuits can also drive similar behaviors, such as enhanced arousal or attention; these processes also may influence choice behavior. These data highlight the formidable challenges ahead in dissecting how appetitive and aversive neural circuits interact to produce a complex and nuanced range of behaviors.

Representations of appetitive and aversive information in the primate orbitofrontal cortex.

Individuals weigh information about both rewarding and aversive stimuli to make adaptive decisions. Most studies of the orbitofrontal cortex (OFC), an area where appetitive and aversive neural subsystems might interact, have focused only on reward. Using a classical conditioning task where novel stimuli are paired with a reward or an aversive air puff, we discovered that two groups of orbitofrontal neurons respond preferentially to conditioned stimuli associated with rewarding and aversive outcomes; however, information about appetitive and aversive stimuli converges on individual neurons from both populations. Therefore, neurons in the OFC might participate in appetitive and aversive networks that track the motivational significance of stimuli even when they vary in valence and sensory modality. Further, we show that these networks, which also extend to the amygdala, exhibit different rates of change during reversal learning. Thus, although both networks represent appetitive and aversive associations, their distinct temporal dynamics might indicate different roles in learning processes.