DREADD activation of the lateral orbitofrontal increases cocaine-taking and cocaine-seeking in male and female rats during intermittent access self-administration under risky conditions.

Addiction is a disorder that can be characterized in part as the constant pursuit of a particular substance despite negative consequences. Although the orbitofrontal cortex (OFC) is known to regulate risk-taking more generally and be critical to the development of addiction, its role in regulating drug use under risk-taking conditions is unknown. To address this, we examined drug-taking and drug-seeking in male and female rats under conditions where cocaine infusions were paired with foot shock punishment 50% of the time and combined this paradigm with cFos immunohistochemistry. We found that rats that showed higher levels of drug-taking and drug-seeking prior to punishment showed decreased responding during self-administration sessions under risky conditions and lower levels of c-Fos expression in the lateral but not medial OFC. However, despite these initial differences in responses to infusions paired with foot shocks, all rats showed decreased responding with additional punishment sessions. We then used chemogenetic viral approaches to examine how altering activity of the lateral OFC affects drug-taking and drug-seeking during punished drug use. Although there was no effect of Gi/o DREADD-mediated inhibition of the lateral OFC on these behaviors, Gq DREADD-mediated activation increased drug-taking and drug-seeking when drug use was associated with foot shock 50% of the time. Interestingly, this manipulation had no effect on non-risky self-administration behavior. These results suggest that the involvement of lateral OFC in cocaine use is context-sensitive and influences decision-making based on negative outcomes.

Prospective, early longitudinal assessment of lymphedema-related quality of life among patients with locally advanced breast cancer: The foundation for building a patient-centered screening program.

BACKGROUND: We examined how breast cancer-related lymphedema (BCRL) affects health-related quality of life (HRQOL), productivity, and compliance with therapeutic interventions to guide structuring BCRL screening programs. METHODS: We prospectively followed consecutive breast cancer patients who underwent axillary lymph node dissection (ALND) with arm volume screening and measures assessing patient-reported health-related quality of life (HRQOL) and perceptions of BCRL care. Comparisons by BCRL status were made with Mann-Whitney U, Chi-square, Fisher's exact, or t tests. Trends over time from ALND were assessed with linear mixed-effects models. RESULTS: With a median follow-up of 8 months in 247 patients, 46% self-reported ever having BCRL, a proportion that increased over time. About 73% reported fear of BCRL, which was stable over time. Further in time from ALND, patients were more likely to report that BCRL screening reduced fear. Patient-reported BCRL was associated with higher soft tissue sensation intensity, biobehavioral, and resource concerns, absenteeism, and work/activity impairment. Objectively measured BCRL had fewer associations with outcomes. Most patients reported performing prevention exercises, but compliance decreased over time; patient-reported BCRL was not associated with exercise frequency. Fear of BCRL was positively associated with performing prevention exercises and using compressive garments. CONCLUSIONS: Both incidence and fear of BCRL were high after ALND for breast cancer. Fear was associated with improved therapeutic compliance, but compliance decreased over time. Patient-reported BCRL was more strongly associated with worse HRQOL and productivity than was objective BCRL. Screening programs must support patients' psychological needs and aim to sustain long-term compliance with recommended interventions.

A Conditioned Place Preference for Heroin Is Signaled by Increased Dopamine and Direct Pathway Activity and Decreased Indirect Pathway Activity in the Nucleus Accumbens.

Repeated pairing of a drug with a neutral stimulus, such as a cue or context, leads to the attribution of the drug's reinforcing properties to that stimulus, and exposure to that stimulus in the absence of the drug can elicit drug-seeking. A principal role for the NAc in the response to drug-associated stimuli has been well documented. Direct and indirect pathway medium spiny neurons (dMSNs and iMSNs) have been shown to bidirectionally regulate cue-induced heroin-seeking in rats expressing addiction-like phenotypes, and a shift in NAc activity toward the direct pathway has been shown in mice following cocaine conditioned place preference (CPP). However, how NAc signaling guides heroin CPP, and whether heroin alters the balance of signaling between dMSNs and iMSNs, remains unknown. Moreover, the role of NAc dopamine signaling in heroin reinforcement is unclear. Here, we integrate fiber photometry for in vivo monitoring of dopamine and dMSN/iMSN calcium activity with a heroin CPP procedure in rats to begin to address these questions. We identify a sensitization-like response to heroin in the NAc, with prominent iMSN activity during initial heroin exposure and prominent dMSN activity following repeated heroin exposure. We demonstrate a ramp in dopamine activity, dMSN activation, and iMSN inactivation preceding entry into a heroin-paired context, and a decrease in dopamine activity, dMSN inactivation, and iMSN activation preceding exit from a heroin-paired context. Finally, we show that buprenorphine is sufficient to prevent the development of heroin CPP and reduce Fos activation in the NAc after conditioning. Together, these data support the hypothesis that an imbalance in NAc activity contributes to the development of drug-cue associations that can drive addiction processes.SIGNIFICANCE STATEMENT The attribution of the reinforcing effects of drugs to neutral stimuli (e.g., cues and contexts) contributes to the long-standing nature of addiction, as re-exposure to drug-associated stimuli can reinstate drug-seeking and -taking even after long periods of abstinence. The NAc has an established role in encoding the value of drug-associated stimuli, and dopamine release into the NAc is known to modulate the reinforcing effects of drugs, including heroin. Using fiber photometry, we show that entering a heroin-paired context is driven by dopamine signaling and NAc direct pathway activation, whereas exiting a heroin-paired context is driven by NAc indirect pathway activation. This study provides further insight into the role of NAc microcircuitry in encoding the reinforcing properties of heroin.

Chemogenetic modulation reveals distinct roles of the subthalamic nucleus and its afferents in the regulation of locomotor sensitization to amphetamine in rats.

The subthalamic nucleus (STN) is a key node in cortico-basal-ganglia thalamic circuits, guiding behavioral output through its position as an excitatory relay of the striatal indirect pathway and its direct connections with the cortex. There have been conflicting results regarding the role of the STN in addiction-related behavior to psychostimulants, and little is known with respect to the role of STN afferents. To address this, we used viral vectors to express DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) in the STN of rats in order to bidirectionally manipulate STN activity during the induction of amphetamine sensitization. In addition, we used a Cre-recombinase dependent Gi/o-coupled DREADD approach to transiently inhibit afferents from ventral pallidum (a subcomponent of the striatal indirect pathway) or the prelimbic cortex (a subcomponent of the cortico-STN hyperdirect pathway). Despite inducing mild hyperactivity in non-drug controls, stimulation of STN neurons with Gq-DREADDs blocked the development and persistence of amphetamine sensitization as well as conditioned responding. In contrast, inhibition of STN neurons with Gi/o-DREADDs enhanced the induction of sensitization without altering its persistence or conditioned responding. Chemogenetic inhibition of afferents from ventral pallidum had no effect on amphetamine sensitization but blocked conditioned responding whereas chemogenetic inhibition of afferents from prelimbic cortex attenuated the persistence of sensitization as well as conditioned responding. These results suggest the STN and its afferents play complex roles in the regulation of amphetamine sensitization and highlight the need for further characterization of how integration of inputs within STN guide behavior.

Strategies for accelerating the implementation of non-intrusive alcohol detection systems in the vehicle fleet.

INTRODUCTION: Crashes involving drinking drivers represent as much as one-third of all fatal crashes around the world. Progress has been made in reducing this toll through a series of interventions that attempt to discourage driving while intoxicated (DWI) and reoffending among drivers who have been convicted of DWI. However, these approaches cannot eliminate the problem. In-vehicle technologies are being developed, such as the Driver Alcohol Detection System for Safety-commonly referred to as DADSS-that have the potential to prevent alcohol-impaired drivers from driving their vehicles. DADSS in-vehicle sensors are designed to quickly detect whether drivers have been drinking and accurately and precisely measure blood or breath alcohol concentration. If the driver's alcohol concentration measures at or above a set limit, the vehicle will be prevented from moving. METHOD: The DADSS technology is expected to be ready for real-world applications in the next few years. The implementation of this technology in vehicles promises to prevent thousands of deaths and injuries every year. This paper investigates approaches that have been used in various countries to accelerate the deployment of innovative vehicle safety technologies beginning with its initial implementation in vehicles through to its more widespread use. RESULTS: Various approaches were identified that can smooth and accelerate the deployment of in-vehicle alcohol detection devices. Recommendations are made regarding the most promising approaches to use initially and over time, as the body of evidence regarding their effectiveness grows. CONCLUSIONS: This paper provides guidelines for how best to stimulate the widespread adoption of in-vehicle alcohol-detection technology as a preventive measure so that its life-saving potential can be realized both in the United States and in other countries that may be open to the implementation of DADSS.

One Is Not Enough: Understanding and Modeling Polysubstance Use.

Substance use disorder (SUD) is a chronic, relapsing disease with a highly multifaceted pathology that includes (but is not limited to) sensitivity to drug-associated cues, negative affect, and motivation to maintain drug consumption. SUDs are highly prevalent, with 35 million people meeting criteria for SUD. While drug use and addiction are highly studied, most investigations of SUDs examine drug use in isolation, rather than in the more prevalent context of comorbid substance histories. Indeed, 11.3% of individuals diagnosed with a SUD have concurrent alcohol and illicit drug use disorders. Furthermore, having a SUD with one substance increases susceptibility to developing dependence on additional substances. For example, the increased risk of developing heroin dependence is twofold for alcohol misusers, threefold for cannabis users, 15-fold for cocaine users, and 40-fold for prescription misusers. Given the prevalence and risk associated with polysubstance use and current public health crises, examining these disorders through the lens of co-use is essential for translatability and improved treatment efficacy. The escalating economic and social costs and continued rise in drug use has spurred interest in developing preclinical models that effectively model this phenomenon. Here, we review the current state of the field in understanding the behavioral and neural circuitry in the context of co-use with common pairings of alcohol, nicotine, cannabis, and other addictive substances. Moreover, we outline key considerations when developing polysubstance models, including challenges to developing preclinical models to provide insights and improve treatment outcomes.

Chemogenetic modulation of accumbens direct or indirect pathways bidirectionally alters reinstatement of heroin-seeking in high- but not low-risk rats.

Opioid addiction has been declared a public health emergency, with fatal overdoses following relapse reaching epidemic proportions and disease-associated costs continuing to escalate. Relapse is often triggered by re-exposure to drug-associated cues, and though the neural substrates responsible for relapse in vulnerable individuals remains ambiguous, the nucleus accumbens (NAc) has been shown to play a central role. NAc direct and indirect pathway medium spiny neurons (dMSNs and iMSNs) can have oppositional control over reward-seeking and associative learning and are critically involved in reinstatement of psychostimulant-seeking. However, whether these pathways similarly regulate reinstatement of opioid-seeking remains unknown, as is their role in modulating motivation to take opioids. Here, we describe a method for classifying addiction severity in outbred rats following intermittent-access heroin self-administration that identifies subgroups as addiction-vulnerable (high-risk) or addiction-resistant (low-risk). Using dual viral-mediated gene transfer of DREADDs, we show that transient inactivation of dMSNs or activation of iMSNs is capable of suppressing cue-induced reinstatement of heroin-seeking in high- but not low-risk rats. Surprisingly, however, the motivation to self-administer heroin was unchanged, indicating a divergence in the encoding of heroin-taking and heroin-seeking in rats. We further show that transient activation of dMSNs or inactivation of iMSNs exacerbates cue-induced reinstatement of heroin-seeking in high- but not low-risk rats, again with no effect on motivation. These findings demonstrate a critical role for dMSNs and iMSNs in encoding vulnerability to reinstatement of heroin-seeking and provide insight into the specific neurobiological changes that occur in vulnerable groups following heroin self-administration.

The impact of cocaine and heroin drug history on motivation and cue sensitivity in a rat model of polydrug abuse.

RATIONALE: Comorbid use of heroin and cocaine is highly prevalent among drug users and can greatly increase addiction risk. Nonetheless, little is known regarding how a multi-drug history impacts motivation and cue responsivity to individual drugs. OBJECTIVE: We used behavioral-economic procedures to examine motivation to maintain drug consumption and tests of drug-seeking to drug-associated cues to assess sensitivity to heroin and cocaine-associated cues in rats that had a self-administration history of heroin, cocaine, or both drugs. RESULTS: Unexpectedly, we found that groups with a polydrug history of heroin and cocaine did not have higher levels of motivation or cue-induced reinstatement of drug-seeking for either cocaine or heroin compared to single drug groups. Nonetheless, we did find drug-specific differences in both economic price and cue sensitivity. Specifically, demand elasticity was lower for cocaine compared to heroin in animals with a single drug history, but not with polydrug groups. In addition, cocaine demand was predictive of the degree of cue-induced reinstatement of drug-seeking for cocaine following extinction, whereas heroin demand was predictive of the degree of reactivity to a heroin-associated cue. Furthermore, although cue reactivity following the initial self-administration phase did not differ across cues and drug history, reactivity to both heroin and cocaine cues was greater during subsequent heroin use compared to cocaine use, and this enhanced reactivity to heroin cues persisted during forced abstinence. CONCLUSIONS: These results indicate that there is a greater motivation to maintain cocaine consumption, but higher sensitivity to drug-associated cues with a history of heroin use, suggesting that cocaine and heroin may drive continued drug use through different behavioral processes.

The paraventricular thalamus is a critical mediator of top-down control of cue-motivated behavior in rats.

Cues in the environment can elicit complex emotional states, and thereby maladaptive behavior, as a function of their ascribed value. Here we capture individual variation in the propensity to attribute motivational value to reward-cues using the sign-tracker/goal-tracker animal model. Goal-trackers attribute predictive value to reward-cues, and sign-trackers attribute both predictive and incentive value. Using chemogenetics and microdialysis, we show that, in sign-trackers, stimulation of the neuronal pathway from the prelimbic cortex (PrL) to the paraventricular nucleus of the thalamus (PVT) decreases the incentive value of a reward-cue. In contrast, in goal-trackers, inhibition of the PrL-PVT pathway increases both the incentive value and dopamine levels in the nucleus accumbens shell. The PrL-PVT pathway, therefore, exerts top-down control over the dopamine-dependent process of incentive salience attribution. These results highlight PrL-PVT pathway as a potential target for treating psychopathologies associated with the attribution of excessive incentive value to reward-cues, including addiction.

Convergent neural connectivity in motor impulsivity and high-fat food binge-like eating in male Sprague-Dawley rats.

Food intake is essential for survival, but maladaptive patterns of intake, possibly encoded by a preexisting vulnerability coupled with the influence of environmental variables, can modify the reward value of food. Impulsivity, a predisposition toward rapid unplanned reactions to stimuli, is one of the multifaceted determinants underlying the etiology of dysregulated eating and its evolving pathogenesis. The medial prefrontal cortex (mPFC) is a major neural director of reward-driven behavior and impulsivity. Compromised signaling between the mPFC and nucleus accumbens shell (NAcSh) is thought to underlie the cognitive inability to withhold prepotent responses (motor impulsivity) and binge intake of high-fat food (HFF) seen in binge eating disorder. To explore the relationship between motor impulsivity and binge-like eating in rodents, we identified high (HI) and low impulsive (LI) rats in the 1-choice serial reaction time task and employed a rat model of binge-like eating behavior. HFF binge rats consumed significantly greater calories relative to control rats maintained on continual access to standard food or HFF. HI rats repeatedly exhibited significantly higher bingeing on HFF vs. LI rats. Next, we employed dual viral vector chemogenetic technology which allows for the targeted and isolated modulation of ventral mPFC (vmPFC) neurons that project to the NAcSh. Chemogenetic activation of the vmPFC to NAcSh pathway significantly suppressed motor impulsivity and binge-like intake for high-fat food. Thus, inherent motor impulsivity and binge-like eating are linked and the vmPFC to NAcSh pathway serves as a 'brake' over both behaviors.

Chemogenetic inhibition of direct pathway striatal neurons normalizes pathological, cue-induced reinstatement of drug-seeking in rats.

Addiction to drugs such as cocaine is marked by cycles of compulsive drug-taking and drug-seeking behavior. Although the transition to addiction is thought to recruit neural processes in dorsal striatum, little is known regarding the role of dorsal striatal projections to the substantia nigra (i.e. the direct pathway) in regulating these behaviors. Combining a Cre-recombinase-dependent chemogenetic approach with a cocaine self-administration paradigm that produces both low-risk and high-risk addiction phenotypes, we examined the effect of transiently decreasing direct pathway activity in the dorsomedial striatum on drug-taking and drug-seeking under conditions of normal and pathological drug use. Surprisingly, transient inhibition of direct pathway striatal neurons had no effect on several measures of addictive behavior during ongoing drug use, including loss of control over drug intake, high motivation to obtain drug and drug use despite negative consequences (i.e. drug use paired with foot shock). However, chemogenetic inhibition of these neurons during reinstatement reduced cue-induced drug-seeking, but only in the high-risk addiction phenotype group. Cue-induced reinstatement was relatively normal in the low-risk addiction phenotype group, as well as following reinstatement to cues associated with sucrose pellet consumption. These results demonstrate that dorsomedial direct pathway striatal neurons play a very specific role in addictive behaviors, which is to regulate the pathological drug-seeking that accompanies relapse.

How early media exposure may affect cognitive function: A review of results from observations in humans and experiments in mice.

Attention deficit hyperactivity disorder (ADHD) is now among the most commonly diagnosed chronic psychological dysfunctions of childhood. By varying estimates, it has increased by 30% in the past 20 years. Environmental factors that might explain this increase have been explored. One such factor may be audiovisual media exposure during early childhood. Observational studies in humans have linked exposure to fast-paced television in the first 3 years of life with subsequent attentional deficits in later childhood. Although longitudinal and well controlled, the observational nature of these studies precludes definitive conclusions regarding a causal relationship. As experimental studies in humans are neither ethical nor practical, mouse models of excessive sensory stimulation (ESS) during childhood, akin to the enrichment studies that have previously shown benefits of stimulation in rodents, have been developed. Experimental studies using this model have corroborated that ESS leads to cognitive and behavioral deficits, some of which may be potentially detrimental. Given the ubiquity of media during childhood, these findings in humansand rodents perhaps have important implications for public health.

Viral strategies for targeting cortical circuits that control cocaine-taking and cocaine-seeking in rodents.

Addiction to cocaine is a chronic disease characterized by persistent drug-taking and drug-seeking behaviors, and a high likelihood of relapse. The prefrontal cortex (PFC) has long been implicated in the development of cocaine addiction, and relapse. However, the PFC is a heterogeneous structure, and understanding the role of PFC subdivisions, cell types and afferent/efferent connections is critical for gaining a comprehensive picture of the contribution of the PFC in addiction-related behaviors. Here we provide an update on the role of the PFC in cocaine addiction from recent work that used viral-mediated optogenetic and chemogenetic tools to study the role of the PFC in drug-taking and drug-seeking behavior in rodents. Following overviews of rodent PFC neuroanatomy and of viral-mediated optogenetic and chemogenetic techniques, we review studies of manipulations within the PFC, followed by a review of work that utilized targeted manipulations to PFC inputs and outputs.

Chemogenetic inhibition reveals midline thalamic nuclei and thalamo-accumbens projections mediate cocaine-seeking in rats.

Drug addiction is a chronic disease that is shaped by alterations in neuronal function within the cortical-basal ganglia-thalamic circuit. However, our understanding of how this circuit regulates drug-seeking remains incomplete, and relapse rates remain high. The midline thalamic nuclei are an integral component of the cortical-basal ganglia-thalamic circuit and are poised to mediate addiction behaviors, including relapse. It is surprising that little research has examined the contribution of midline thalamic nuclei and their efferent projections in relapse. To address this, we expressed inhibitory, Gi/o -coupled DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) in a subset of the midline thalamic nuclei or in midline thalamic nuclei neurons projecting to either the nucleus accumbens or the amygdala. We examined the effect of transiently decreasing activity of these neuronal populations on cue-induced and cocaine-primed reinstatement of cocaine-seeking. Reducing activity of midline thalamic nuclei neurons attenuated both cue-induced and cocaine-primed reinstatement, but had no effect on cue-induced reinstatement of sucrose-seeking or locomotor activity. Interestingly, attenuating activity of efferent projections from the anterior portion of midline thalamic nuclei to the nucleus accumbens blocked cocaine-primed reinstatement but enhanced cue-induced reinstatement. Decreasing activity of efferent projections from either the posterior midline thalamic nuclei to the nucleus accumbens or the midline thalamic nuclei to amygdala had no effect. These results reveal a novel contribution of subsets of midline thalamic nuclei neurons in drug-seeking behaviors and suggest that modulation of midline thalamic nuclei activity may be a promising therapeutic target for preventing relapse.

Excessive Sensory Stimulation during Development Alters Neural Plasticity and Vulnerability to Cocaine in Mice.

Early life experiences affect the formation of neuronal networks, which can have a profound impact on brain function and behavior later in life. Previous work has shown that mice exposed to excessive sensory stimulation during development are hyperactive and novelty seeking, and display impaired cognition compared with controls. In this study, we addressed the issue of whether excessive sensory stimulation during development could alter behaviors related to addiction and underlying circuitry in CD-1 mice. We found that the reinforcing properties of cocaine were significantly enhanced in mice exposed to excessive sensory stimulation. Moreover, although these mice displayed hyperactivity that became more pronounced over time, they showed impaired persistence of cocaine-induced locomotor sensitization. These behavioral effects were associated with alterations in glutamatergic transmission in the nucleus accumbens and amygdala. Together, these findings suggest that excessive sensory stimulation in early life significantly alters drug reward and the neural circuits that regulate addiction and attention deficit hyperactivity. These observations highlight the consequences of early life experiences and may have important implications for children growing up in today's complex technological environment.

Corticostriatal Afferents Modulate Responsiveness to Psychostimulant Drugs and Drug-Associated Stimuli.

The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) are both integral components of the corticobasal ganglia-thalamic circuitry that regulates addiction-related behaviors. However, the role of afferent inputs from mPFC to NAc in these behaviors is unclear. To address this, we used a Cre-recombinase-dependent viral vector approach to express G(i/o)-coupled DREADDs (designer receptors exclusively activated by designer drugs) selectively in mPFC neurons projecting to the NAc and examined the consequences of attenuating activity of these neurons on the induction of amphetamine sensitization and on drug taking and drug seeking during cocaine self-administration. Surprisingly, decreasing mPFC afferent activity to the NAc only transiently reduced locomotor sensitization and had no effect on drug taking during cocaine self-administration. However, inhibiting corticostriatal afferent activity during sensitization subsequently enhanced conditioned responding. In addition, this manipulation during drug self-administration resulted in slower rates of extinction and increased responding during drug prime-induced reinstatement-an effect that was normalized by inhibiting these corticostriatal afferents immediately before the drug prime. These results suggest that dampening cortical control over the NAc during drug exposure may lead to long-term changes in the ability of drugs and associated stimuli to drive behavior that has important implications for guiding treatments to prevent relapse.

Prospective study of a proactive palliative care rounding intervention in a medical ICU.

PURPOSE: To evaluate the effects of a palliative care intervention on clinical and family outcomes, and palliative care processes. METHODS: Prospective, before-and-after interventional study enrolling patients with high risk of mortality, morbidity, or unmet palliative care needs in a 24-bed academic intensive care unit (ICU). The intervention involved a palliative care clinician interacting with the ICU physicians on daily rounds for high-risk patients. RESULTS: One hundred patients were enrolled in the usual care phase, and 103 patients were enrolled during the intervention phase. The adjusted likelihood of a family meeting in ICU was 63% higher (RR 1.63, 95% CI 1.14-2.07, p = 0.01), and time to family meeting was 41% shorter (95% CI 52-28% shorter, p < 0.001). Adjusted ICU length of stay (LOS) was not significantly different between the two groups (6% shorter, 95% CI 16% shorter to 4% longer, p = 0.22). Among those who died in the hospital, ICU LOS was 19% shorter in the intervention (95% CI 33-1% shorter, p = 0.043). Adjusted hospital LOS was 26% shorter (95% CI 31-20% shorter, p < 0.001) with the intervention. Post-traumatic stress disorder (PTSD) symptoms were present in 9.1% of family respondents during the intervention versus 20.7% prior to the intervention (p = 0.09). Mortality, family depressive symptoms, family satisfaction and quality of death and dying did not significantly differ between groups. CONCLUSIONS: Proactive palliative care involvement on ICU rounds for high-risk patients was associated with more and earlier ICU family meetings and shorter hospital LOS. We did not identify differences in family satisfaction, family psychological symptoms, or family-rated quality of dying, but had limited power to detect such differences.

Design and Outcome of a Certification Preparation Program for Outpatient Nurses.

This article presents the design, implementation, and outcomes of a certification preparation program for nurses working in an outpatient clinic. A nurse educator designed curriculum using the Certified Breast Care Nurse test blueprint. Nurse administrators provided the resources and the staff coverage to allow all staff members to attend the sessions without disruption to patient care. This outpatient center has achieved and sustained 100% certification among eligible nurses over the past 5 years.

Inhibition of IL-6 signaling pathway by curcumin in uterine decidual cells.

IL-6 is a multifunctional pro-inflammatory cytokine and has been implicated in many gestational disorders including preterm birth. Currently, there are no appropriate therapeutic interventions available to circumvent inflammatory-mediated gestational disorders. Therefore, the goal of this study was to identify a safe and effective pharmacological compound to counterbalance inflammatory responses in the uterus. Curcumin, a naturally-occurring polyphenolic compound, has been widely used in alternative medicine to treat inflammatory diseases. However, the anti-inflammatory effect of curcumin has not been explored in uterine decidual cells, a major source of IL-6. Therefore, we examined the effect of curcumin on IL-6 expression using two types of uterine decidual cells 1) HuF cells, primary human fibroblast cells obtained from the decidua parietalis; 2) UIII cells, a rodent non-transformed decidual cell line. Curcumin treatment completely abrogated the expression of IL-1ß-induced IL-6 in these cells. Curcumin also strongly inhibited the expression of gp130, a critical molecule in IL-6 signaling, whereas expression of IL-6R and sIL-6R was not affected. Curcumin also inhibited phosphorylation and nuclear localization of STAT3, a well-known downstream mediator of IL-6 signaling. Furthermore, curcumin attenuated IL-1ß-induced IL-6 promoter reporter activity suggesting transcriptional regulation. To further understand whether NF-Ò¡B is involved in this inhibition, we examined the effect of curcumin on the expression of p50 and p65 subunits of NF-Ò¡B in decidual cells. Expression of IL-1ß-induced p50 mRNA was repressed by curcumin while p65 mRNA was not affected. However, curcumin treatment dramatically inhibited both p50 and p65 protein levels and prevented its nuclear localization. This effect is at least partly mediated through the deactivation of IKK, since IL-1ß-induced IKKα/ß phosphorylation is decreased upon curcumin treatment. Our results not only revealed molecular mechanisms underlying curcumin action in uterine decidual cells but also suggest that this compound may have therapeutic potential for the prevention of inflammation-mediated preterm birth and other gestational disorders.