Non-human animal studies outline precise mechanisms of central mu-opioid regulation of pain, stress, affiliation and reward processing. In humans, pharmacological blockade with non-selective opioid ...antagonists such as naloxone and naltrexone is typically used to assess involvement of the mu-opioid system in such processing. However, robust estimates of the opioid receptor blockade achieved by opioid antagonists are missing. Dose and timing schedules are highly variable and often based on single studies. Here, we provide a detailed analysis of central opioid receptor blockade after opioid antagonism based on existing positron emission tomography data. We also create models for estimating opioid receptor blockade with intravenous naloxone and oral naltrexone. We find that common doses of intravenous naloxone (0.10-0.15 mg/kg) and oral naltrexone (50 mg) are more than sufficient to produce full blockade of central MOR (>90% receptor occupancy) for the duration of a typical experimental session (~60 min), presumably due to initial super saturation of receptors. Simulations indicate that these doses also produce high KOR blockade (78-100%) and some DOR blockade (10% with naltrexone and 48-74% with naloxone). Lower doses (e.g., 0.01 mg/kg intravenous naloxone) are estimated to produce less DOR and KOR blockade while still achieving a high level of MOR blockade for ~30 min. The models and simulations form the basis of two novel web applications for detailed planning and evaluation of experiments with opioid antagonists. These tools and recommendations enable selection of appropriate antagonists, doses and assessment time points, and determination of the achieved receptor blockade in previous studies.
Objective
To assess the impact of a novel flipped‐classroom (FC) otolaryngology resident didactic curriculum on resident learning.
Methods
Based on the preferences elicited in a survey of preferred ...learning styles of residents, a hybrid web‐based and in‐person FC otolaryngology didactic curriculum was implemented over a 6‐month period in 2020–2021.
Resident reactions to the new curriculum were assessed via a second survey. Kruskal Wallis tests were used to compare mean stanine scores on the Otolaryngology Training Examination (OTE) exam for topics taught in the new format with topics delivered in the old format.
Results
After instituting the curriculum reform, engagement in at least a moderate amount of the pre‐didactic work and synchronous case discussions was reported by 67% and 88% of the residents, respectively. After the curriculum change, residents in years PGY2 and above reported statistically significant increases in self‐reported ability to retain information from didactics, to feel prepared for the OTE, and to feel confident in fund of knowledge (p < 0.001, p = 0.004, and p = 0.004, respectively). Compared to the prior year, mean stanine increased on OTE scores for residents in years PGY2‐PGY5 to a statistically significant degree (5.45 vs. 4.41, p = 0.001) for the topics delivered in the new format compared to topics delivered in the traditional format (5.13 vs. 4.70, p = 0.07).
Conclusion
By organizing a didactic curriculum through online modules that incorporate pre‐recorded lectures and external resources, residents reported and demonstrated improved knowledge retention.
Level of Evidence
NA Laryngoscope, 133:2129–2134, 2023
This study examined the impact of a novel, flipped‐classroom otolaryngology resident didactic curriculum. After curriculum changes were instituted, residents reported increased ability to retain information and scores on the Otolaryngology Training Examination were statistically significantly improved.
Symmetry and symmetry breaking concepts from physics and biology are applied to the problem of cancer. Three categories of symmetry breaking in cancer are examined: combinatorial, geometric, and ...functional. Within these categories, symmetry breaking is examined for relevant cancer features, including epithelial-mesenchymal transition (EMT); tumor heterogeneity; tensegrity; fractal geometric and information structure; functional interaction networks; and network stabilizability and attack tolerance. The new cancer symmetry concepts are relevant to homeostasis loss in cancer and to its origin, spread, treatment and resistance. Symmetry and symmetry breaking could provide a new way of thinking and a pathway to a solution of the cancer problem.
Background Cocaine users not seeking treatment have increased regional brain mu-opioid receptor (mOR) binding that correlates with cocaine craving and tendency to relapse. In cocaine-abusing ...outpatients in treatment, the relationship of mOR binding and treatment outcome is unknown. Methods We determined whether regional brain mOR binding before treatment correlates with outcome and compared it with standard clinical predictors of outcome. Twenty-five individuals seeking outpatient treatment for cocaine abuse or dependence (DSM-IV) received up to 12 weeks of cognitive-behavioral therapy and cocaine abstinence reinforcement, whereby each cocaine-free urine was reinforced with vouchers redeemable for goods. Regional brain mOR binding was measured before treatment using positron emission tomography with 11 C-carfentanil (a selective mOR agonist). Main outcome measures were: 1) overall percentage of urines positive for cocaine during first month of treatment; and 2) longest duration (weeks) of abstinence from cocaine during treatment, all verified by urine toxicology. Results Elevated mOR binding in the medial frontal and middle frontal gyri before treatment correlated with greater cocaine use during treatment. Elevated mOR binding in the anterior cingulate, medial frontal, middle frontal, middle temporal, and sublobar insular gyri correlated with shorter duration of cocaine abstinence during treatment. Regional mOR binding contributed significant predictive power for treatment outcome beyond that of standard clinical variables such as baseline drug and alcohol use. Conclusions Elevated mOR binding in brain regions associated with reward sensitivity is a significant independent predictor of treatment outcome in cocaine-abusing outpatients, suggesting a key role for the brain endogenous opioid system in cocaine addiction.
Background: The endogenous opioid system plays a significant role in alcohol dependence. The goal of the current study was to investigate regional brain mu‐opioid receptor (MOR) and delta‐opioid ...receptor (DOR) availability in recently abstinent alcohol‐dependent and age‐matched healthy control men and women with positron emission tomography (PET) imaging.
Methods: Alcohol‐dependent subjects completed an inpatient protocol, which included medically supervised withdrawal and PET imaging on day 5 of abstinence. Control subjects completed PET imaging following an overnight stay. PET scans with the MOR‐selective ligand 11Ccarfentanil (CFN) were completed in 25 alcohol‐dependent and 30 control subjects. Most of these same subjects (20 alcohol‐dependent subjects and 18 controls) also completed PET scans with the DOR‐selective ligand 11Cmethylnaltrindole (MeNTL).
Results: Volumes of interest and statistical parametric mapping analyses indicated that alcohol‐dependent subjects had significantly higher 11CCFN binding potential (BPND) than healthy controls in multiple brain regions including the ventral striatum when adjusting for age, gender, and smoking status. There was an inverse relationship between 11CCFN BPND and craving in several brain regions in alcohol‐dependent subjects. Groups did not differ in 11CMeNTL BPND; however, 11CMeNTL BPND in caudate was positively correlated with recent alcohol drinking in alcohol‐dependent subjects.
Conclusions: Our observation of higher 11CCFN BPND in alcohol‐dependent subjects can result from up‐regulation of MOR and/or reduction in endogenous opioid peptides following long‐term alcohol consumption, dependence, and/or withdrawal. Alternatively, the higher 11CCFN BPND in alcohol‐dependent subjects may be an etiological difference that predisposed these individuals to alcohol dependence or may have developed as a result of increased exposure to childhood adversity, stress, and other environmental factors known to increase MOR. Although the direction of group differences in 11CMeNTL BPND was similar in many brain regions, differences did not achieve statistical significance, perhaps as a result of our limited sample size. Additional research is needed to further clarify these relationships. The finding that alcohol‐dependent subjects had higher 11CCFN BPND is consistent with a prominent role of the MOR in alcohol dependence.
Summary Investigators have administered the opioid receptor antagonist, naloxone, to interrogate the hypothalamic-pituitary-adrenal (HPA) axis response under the assumption that this technique ...provides a measure of endogenous opioid activity. However it has never been tested whether provocation of the HPA axis with naloxone provides a surrogate marker for direct measurement of endogenous opioid activity using PET imaging as the gold standard. To test this hypothesis, eighteen healthy subjects underwent a PET scan with the mu-opioid receptor (MOR) selective ligand 11 Ccarfentanil (CFN). The following day ACTH and cortisol responses were assessed using a technique which allows administration of 5 incremental doses of naloxone (0, 25, 50, 100 and 250 μg/kg) in a single session. Relationships between ACTH and cortisol responses and 11 CCFN binding potential (BPND ) were examined in 5 brain regions involved in the regulation of the HPA axis and/or regions with high concentrations of MOR. All subjects mounted graded ACTH and cortisol responses to naloxone administrations. There were significant negative relationships between cortisol response to naloxone and 11 CCFN BPND in ventral striatum, putamen and caudate. When sex and smoking were added as covariates to the model, these correlations were strengthened and there was a significant correlation with the hypothalamus. There were no significant correlations between ACTH and any volumes of interest. The opioid receptor antagonist naloxone is not merely a non-specific pharmacologic activator of the HPA axis; it provides information about individual differences in opioid receptor availability.
Recent evidence places the FRAP/mTOR kinase downstream of the phosphatidyl inositol 3-kinase/Akt-signaling pathway, which is up-regulated in multiple cancers because of loss of the PTEN tumor ...suppressor gene. We performed biological and biochemical studies to determine whether PTEN-deficient cancer cells are sensitive to pharmacologic inhibition of FRAP/mTOR by using the rapamycin derivative CCI-779. In vitro and in vivo studies of isogenic PTEN+/+and PTEN-/-mouse cells as well as human cancer cells with defined PTEN status showed that the growth of PTEN null cells was blocked preferentially by pharmacologic FRAP/mTOR inhibition. Enhanced tumor growth caused by constitutive activation of Akt in PTEN+/+cells also was reversed by CCI-779 treatment, indicating that FRAP/mTOR functions downstream of Akt in tumorigenesis. Loss of PTEN correlated with increased S6 kinase activity and phosphorylation of ribosomal S6 protein, providing evidence for activation of the FRAP/mTOR pathway in these cells. Differential sensitivity to CCI-779 was not explained by differences in biochemical blockade of the FRAP/mTOR pathway, because S6 phosphorylation was inhibited in sensitive and resistant cell lines. These results provide rationale for testing FRAP/mTOR inhibitors in PTEN null human cancers.
11CP943 is a new radioligand recently developed to image and quantify serotonin 5-Hydroxytryptamine (5-HT1B) receptors with positron emission tomography (PET). The purpose of this study was to ...evaluate 11CP943 for this application in humans, and to determine the most suitable quantification method. Positron emission tomography data and arterial input function measurements were acquired in a cohort of 32 human subjects. Using arterial input functions, compartmental modeling, the Logan graphical analysis, and the multilinear method MA1 were tested. Both the two tissue-compartment model and MA1 provided good fits of the PET data and reliable distribution volume estimates. Using the cerebellum as a reference region, BPND binding potential estimates were computed. 11CP943 BPND estimates were significantly correlated with in vitro measurements of the density of 5-HT1B receptors, with highest values in the occipital cortex and pallidum. To evaluate noninvasive methods, two- and three-parameter graphical analyses, Simplified Reference Tissue Models (SRTM and SRTM2), and Multilinear Reference Tissue Models (MRTM and MRTM2) were tested. The MRTM2 model provided the best correlation with MA1 binding-potential estimates. Parametric images of the volume of distribution or binding potential of 11CP943 could be computed using both MA1 and MRTM2. The results show that 11CP943 provides quantitative measurements of 5-HT1B binding potential.
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