The Foundational Science of Endogenous Opioids and Their Receptors.

The function of endogenous opioids spans from initiating behaviors that are critical for survival, to responding to rapidly changing environmental conditions. A network of interconnected systems throughout the body characterizes the endogenous opioid system (EOS). EOS receptors for beta-endorphin, enkephalin, dynorphin, and endomorphin underpin the diverse functions of the EOS across biological systems. This chapter presents a succinct yet comprehensive summary of the structure of the EOS, EOS receptors, and their relationship to other biological systems.

Depression, Cancer, Inflammation, and Endogenous Opioids: Pathogenic Relationships and Therapeutic Options.

Endogenous opioids and their associated receptors form a system that maintains survival by positively reinforcing behaviors that are vital to life. Cancer and cancer treatment side effects capitalize on this system pathogenically, leading to maladaptive biological responses (e.g., inflammation), as well as cognitive and emotional consequences, most notably depression. Psychologists who treat people with cancer frequently find depression to be a primary target for intervention. However, in people with cancer, the etiology of depression is unique and complex. This complexity necessitates that psycho-oncologists have a fundamental working knowledge of the biological substrates that underlie depression/cancer comorbidity. Building on other chapters in this volume pertaining to cancer and endogenous opioids, this chapter focuses on the clinical applications of basic scientific findings.

Introduction to the Volume: The Journey Ahead.

The endogenous opioid system (EOS) is complex. The line of research contributing to our current body of knowledge about this system is diverse, as are the ways in which endogenous opioids affect human health and behavior. This chapter serves as an introduction to the edited volume. It includes commentary about the current public discourse related to opioids, the rationale for this book, and the unique contributions of each chapter within this volume.

Longitudinal investigation of the factor structure of the Parkinson's disease activities of daily living, interference and dependence instrument.

The Parkinson's Disease Activities of Daily Living, Interference, and Dependence Instrument© (PD-AID) is a patient-reported outcome (PRO) instrument, recently developed to assess the clinical benefit of Parkinson's Disease (PD) treatment. The PD-AID consists of morning and evening assessments, administered daily. To benefit from the full set of the repeated observations over time, analytic approaches that account for both within- and between-individual variability are required. The current study aimed to employ the advantages of exploratory Multilevel Factor Analysis (MFA) on data collected from 93 participants with moderate to advanced PD, currently using and responding to Levodopa (L-Dopa), who completed the PD-AID twice daily as part of a prospective, non-intervention, observational study for ~28 days. Average daily completion rates were comparable for the Morning and the Evening PD-AID (78% and 74%, respectively). The intraclass correlation coefficients for the Morning and Evening PD-AID items were in the range of 0.70-0.90, with an average of 0.81 for the Morning PD-AID items and 0.83 for the Evening PD-AID items, suggesting that most variability (81%-83%) in responses was due to between-individual variability. For the Morning PD-AID, one factor (including nine out of 10 Morning PD-AID items) emerged at the between-individual level and four factors (core physical actions, basic self-care activities, feeding, and interference & dependence) at the within-individual level. For the Evening PD-AID, there were four between-individual factors (basic activities of daily living ADLs, life interference, impact on planning, and emotional consequences) and five within-individual factors (basic ADLs, toileting, life interference, medication planning, and emotional impact). The factors had high reliability.

Peppers in Diet: Genome-Wide Transcriptome and Metabolome Changes in Drosophila melanogaster.

The habanero pepper (Capsicum chinense) is an increasingly important spice and vegetable crop worldwide because of its high capsaicin content and pungent flavor. Diets supplemented with the phytochemicals found in habanero peppers might cause shifts in an organism's metabolism and gene expression. Thus, understanding how these interactions occur can reveal the potential health effects associated with such changes. We performed transcriptomic and metabolomic analyses of Drosophila melanogaster adult flies reared on a habanero pepper diet. We found 539 genes/59 metabolites that were differentially expressed/accumulated in flies fed a pepper versus control diet. Transcriptome results indicated that olfactory sensitivity and behavioral responses to the pepper diet were mediated by olfactory and nutrient-related genes including gustatory receptors (Gr63a, Gr66a, and Gr89a), odorant receptors (Or23a, Or59a, Or82a, and Orco), and odorant-binding proteins (Obp28a, Obp83a, Obp83b, Obp93a, and Obp99a). Metabolome analysis revealed that campesterol, sitosterol, and sucrose were highly upregulated and azelaic acid, ethyl phosphoric acid, and citric acid were the major metabolites downregulated in response to the habanero pepper diet. Further investigation by integration analysis between transcriptome and metabolome data at gene pathway levels revealed six unique enriched pathways, including phenylalanine metabolism; insect hormone biosynthesis; pyrimidine metabolism; glyoxylate, and dicarboxylate metabolism; glycine, serine, threonine metabolism; and glycerolipid metabolism. In view of the transcriptome and metabolome findings, our comprehensive analysis of the response to a pepper diet in Drosophila have implications for exploring the molecular mechanism of pepper consumption.

A Retrospective Study of Brain Metastases From Solid Malignancies: The Effect of Immune Checkpoint Inhibitors.

INTRODUCTION: Brain metastases (BM) are associated with dismal prognosis, and there is a dearth of effective systemic therapy. In this study, patients with BM from multiple solid tumors were identified from TriNetX databases, their clinicopathological features were evaluated, and the effects of immune checkpoint inhibitor (ICI) therapy were assessed. METHODS: Variables, including median overall survival (OS), Eastern Cooperative Oncology Group (ECOG) performance status, primary diagnosis, and date of diagnosis, were retrieved from TriNetX, a real-world database. Kaplan-Meier plots and log-rank tests were applied to assess significance of differences in survival. Hazard ratio (HR) and 95% confidence interval (CI) values were calculated. All patient data were deidentified. RESULTS: A total of 227,255 patients with BM were identified in the TriNetX database; median OS was 12.3 months from initial cancer diagnosis and 7.1 months from development of BM. OS of BM from nonsmall-cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), melanoma, and renal cell carcinoma (RCC) were 8.7, 14.7, 17.8, and 15.6 months, respectively. After matching patient baseline characteristics, OS of cohorts with or without exposure to ICIs was evaluated. For all types of cancer, median OS durations for the ICI and no-ICI cohorts were 14.0 and 7.9 months, respectively (HR: 0.88; 95% CI: 0.85-0.91). More specifically, OS was remarkably prolonged in patients with NSCLC (14.4 vs. 8.2 months; HR: 0.86; 95% CI: 0.82-0.90), TNBC (23.9 vs. 11.6 months; HR: 0.87; 95% CI: 0.82-0.92), and melanoma (27.6 vs. 16.8 months; HR: 0.80; 95% CI: 0.73-0.88) if patients had exposure to ICIs. In contrast, there was no significant difference in OS of patients with RCC treated with and without ICIs (16.7 vs. 14.0 months; HR: 0.96; 95% CI: 0.86-1.10). CONCLUSIONS: Overall, BM indicates poor patient outcome. Treatment with ICIs improves survival of patients with NSCLC, TNBC, and melanoma and BM; however, no significant improvement was observed in RCC. Investigations to identify prognostic features, oncogenomic profiles, and predictive biomarkers are warranted.

Hydroxychloroquine in Hospitalized Patients with COVID-19: Real-World Experience Assessing Mortality.

INTRODUCTION: Hydroxychloroquine (HCQ) for coronavirus disease 2019 (COVID-19) is presently being used off-label or within a clinical trial. OBJECTIVES: We investigated a multinational database of patients with COVID-19 with real-world data containing outcomes and their relationship to HCQ use. The primary outcome was all-cause mortality within 30 days of follow-up. METHODS: This was a retrospective cohort study of patients receiving HCQ within 48 hours of hospital admission. Medications, preexisting conditions, clinical measures on admission, and outcomes were recorded. RESULTS: Among patients with a diagnosis of COVID-19 in our propensity-matched cohort, the mean ages ± SD were 62.3 ± 15.9 years (53.7% male) and 61.9 ± 16.0 years (53.0% male) in the HCQ and no-HCQ groups, respectively. There was no difference in overall 30-day mortality between the HCQ and no-HCQ groups (HCQ 13.1%, n=367; no HCQ 13.6%, n=367; odds ratio 0.95, 95% confidence interval 0.62-1.46) after propensity matching. Although statistically insignificant, the HCQ-azithromycin (AZ) group had an overall mortality rate of 14.6% (n=199) compared with propensity-matched no-HCQ-AZ cohort's rate of 12.1% (n=199, OR 1.24, 95% CI 0.70-2.22). Importantly, however, there was no trend in this cohort's overall mortality/arrhythmogenesis outcome (HCQ-AZ 17.1%, no HCQ-no AZ 17.1%; OR 1.0, 95% CI 0.6-1.7). CONCLUSIONS: We report from a large retrospective multinational database analysis of COVID-19 outcomes with HCQ and overall mortality in hospitalized patients. There was no statistically significant increase in mortality and mortality-arrhythmia with HCQ or HCQ-AZ.

Effect of Pepper-Containing Diets on the Diversity and Composition of Gut Microbiome of Drosophila melanogaster.

One of the greatest impacts on the gastrointestinal microbiome is diet because the host and microbiome share the same food source. In addition, the effect of diet can diverge depending on the host genotype. Diets supplemented with phytochemicals found in peppers might cause shifts in the microbiome. Thus, understanding how these interactions occur can reveal potential health implications associated with such changes. This study aims to explore the gut microbiome of different Drosophila genetic backgrounds and the effects of dietary pepper treatments on its composition and structure. We analyzed the gut microbiomes of three Drosophila melanogaster genetic backgrounds (Canton-S, Oregon-RC, and Berlin-K) reared on control and pepper-containing diets (bell, serrano, and habanero peppers). Results of 16S rRNA gene sequencing revealed that the variability of Drosophila gut microbiome can be driven mainly by genetic factors. When the abundance of these communities is considered, pepper-containing diets also appear to have an effect. The most relevant change in microbial composition was the increment of Lactobacillaceae and Acetobacteraceae abundance in the pepper-containing diets in comparison with the controls in Oregon-RC and Berlin-K. Regression analysis demonstrated that this enhancement was associated with the content of phenolic compounds and carotenoids of the peppers utilized in this study; specifically, to the concentration of ß-carotene, ß-cryptoxanthin, myricetin, quercetin, and apigenin.

Effect of ghost pepper on cell proliferation, apoptosis, senescence and global proteomic profile in human renal adenocarcinoma cells.

Chili peppers are an important constituent of many foods and contain medicinally valuable compounds, such as capsaicin and dihydrocapsaicin. As various dietary botanicals have anticancer properties, this study was aimed to examine the effect of Ghost pepper (Bhut Jolokia), one of the hottest chili peppers in the world, on cell proliferation, apoptosis, senescence and the global proteomic profile in human renal cell adenocarcinoma in vitro. 769-P human renal adenocarcinoma cells were cultured on RPMI-1640 media supplemented with fetal bovine serum (10%) and antibiotic-antimycotic solution (1%). Treatment stock solutions were prepared in ethanol. Cell proliferation was tested with phenol red-free media with capsaicin (0-400 µM), dihydrocapsaicin (0-400 µM), capsaicin + dihydrocapsaicin (5:1), and dry Ghost peppers (0-3 g L-1) for 24, 48 and 72 h. Polycaspase and senescence associated-beta-galactosidase (SA-beta-gal) activities were tested with capsaicin (400 µM), dihydrocapsaicin (400 µM), capsaicin (400 µM) + dihydrocapsaicin (80 µM), and ghost pepper (3 g L-1) treatments. Global proteomic profile of cells in control and ghost pepper treatment (3 g L-1) was analyzed after 6 h by a shotgun proteomic approach using tandem mass spectrometry. At 24 h after treatment (24 HAT), relative to control, cell proportion with capsaicin (400 µM), dihydrocapsaicin (400 µM), capsaicin (400 µM) + dihydrocapsaicin (80 µM), and ghost pepper (3 g L-1) treatments was reduced to 36%, 18%, 33% and 20%, respectively, and further reduced at 48 and 72 HAT. All treatments triggered an early polycaspase response. SA-beta-gal activity was normal or suppressed with all treatments. About 68,220 protein isoforms were identified by shotgun proteomic approach. Among these, about 8.2% were significantly affected by ghost pepper. Ghost pepper regulated various proteins involved in intrinsic and extrinsic apoptotic pathways, Ras, Rb/E2F, p53, TGF-beta, WNT-beta catenin, and calcium induced cell death pathways. Ghost pepper also induced changes in proteins related to methylation, acetylation, genome stability, cell cycle check points, carbohydrate, protein and other metabolism and cellular mechanisms. Ghost pepper exhibited antiproliferation activity by inducing apoptosis through a complex network of proteins in human renal cell adenocarcinoma in vitro.

Combination Drug Therapy of Pioglitazone and D-cycloserine Attenuates Chronic Orofacial Neuropathic Pain and Anxiety by Improving Mitochondrial Function Following Trigeminal Nerve Injury.

OBJECTIVES: The study aim was to determine how peripheral trigeminal nerve injury affects mitochondrial respiration and to test efficacy of combined treatment with 2 Federal Drug Administration approved drugs with potential for improving mitochondrial bioenergetics, pain and anxiety-related behaviors in a chronic orofacial neuropathic pain mouse model. METHODS: Efficacy of (R)-(+)-4-amino-3-isoxazolidinone (D-cycloserine, DCS), an N-Methyl-D-aspartate antagonist/agonist, and Pioglitazone (PIO), a selective agonist of nuclear receptor peroxisome proliferator-activated receptor gamma was investigate in the trigeminal inflammatory compression (TIC) neuropathic nerve injury mouse model. Combined low doses of these drugs (80 mg/kg DCS and 100 mg/kg PIO) were given as a single bolus or daily for 7 days post-TIC to test ability to attenuate neuropathic nociceptive and associated cognitive dependent anxiety behaviors. In addition, beneficial effects of the DCS/PIO drug combination were explored ex vivo in isolated cortex/brainstem mitochondria at 28 weeks post-TIC. RESULTS: The DCS/PIO combination not only attenuated orofacial neuropathic pain and anxiety-related behaviors associated with trigeminal nerve injury, but it also improved mitochondrial bioenergetics. DISCUSSION: The DCS/PIO combination uncoupled mitochondrial respiration in the TIC model to improve cortical mitochondrial dysfunction, as well as reduced nociceptive and anxiety behaviors present in mice with centralized chronic neuropathic nerve injury. Combining these drugs could be a beneficial treatment for patients with depression, anxiety, or other psychological conditions due to their chronic pain status.

Specific phobia in youth: phenomenology and psychological characteristics.

Sociodemographic and psychological characteristics of 62 youth with animal and natural environment types of specific phobia were examined in a treatment-seeking sample. Differences due to age, sex, ethnicity, family structure, and family socioeconomic status were not found between youth with the two types of specific phobia. Moreover, differences were not obtained between the two groups in the clinical severity of their phobias, the perceived dangerousness of the feared outcomes associated with their phobias, the perceived levels of coping with their phobias, or overall fearfulness. However, differences between youth with the two types of specific phobias were found on somatic/anxious symptoms, depressive symptoms, and life satisfaction. In addition, differences were noted on withdrawn, somatic complaints, anxious/depressed symptoms, and social problems as reported by the mothers of these youngsters. Finally, differences in the percent of co-occurring anxiety disorders between youth with the two types of specific phobia were found. On all of the domains in which differences were found, youth with the natural environment type fared more poorly than those with the animal type. These findings converge with those obtained in treatment studies which indicate that youth with the natural environment type are more difficult to treat than youth with the animal type.

Testosterone and depression: systematic review and meta-analysis.

BACKGROUND: Studies suggest that testosterone (TT) replacement may have an antidepressant effect in depressed patients. OBJECTIVE: The objective of this study was to explore the effect of TT administration on depression using both a systematic review of the literature and a meta-analysis. METHODOLOGY: A search was conducted of MEDLINE, the Clinical Trials Registry, and Cochrane Central for English-language publications concerning randomized, placebo-controlled trials involving use of TT therapy in depressed patients. We searched for additional trials in the individual reference lists of the articles identified in the search. A study was judged to be relevant for inclusion in this review and meta-analysis if it reported original data from a controlled trial comparing use of TT and placebo in patients diagnosed with a depressive disorder according to DSM criteria, and the treatment response was evaluated according to changes on the Hamilton Rating Scale for Depression (HAM-D). We extracted the following data from the identified studies: study source, total number of participants in the study and in each treatment group, participants' ages, number of participants with a diagnosis of hypogonadism or HIV/AIDS, study duration, type of intervention, and change in HAM-D scores in the groups receiving TT versus placebo. The meta-analysis evaluated the effect of TT replacement on response in depressed patients as measured by change in HAM-D scores in the available placebo-controlled, randomized clinical trails. RESULTS: Seven studies (N=364) were identified that included a placebo-control group in a double-blind design. Eligibility criteria were clearly reported in all trials. Meta-analysis of the data from these seven studies showed a significant positive effect of TT therapy on HAM-D response in depressed patients when compared with placebo (z=4.04, P<0.0001). Subgroup analysis also showed a significant response in the subpopulations with hypogonadism (z=3.84, P=0.0001) and HIV/AIDS (z=3.33, P=0.0009) as well as in patients treated with TT gel (z=2.32, P=0.02). CONCLUSIONS: TT may have an antidepressant effect in depressed patients, especially those with hypogonadism or HIV/AIDS and elderly subpopulations. The route by which TT is administered may play a role in treatment response.

One-session treatment of specific phobias in youth: a randomized clinical trial in the United States and Sweden.

One hundred and ninety-six youth, ages 7-16, who fulfilled Diagnostic and Statistical Manual of Mental Disorders (4th ed.) criteria for various specific phobias were randomized to a one-session exposure treatment, education support treatment, or a wait list control group. After the waiting period, the wait list participants were offered treatment and, if interested, rerandomized to 1 of the 2 active treatments. The phobias were assessed with semistructured diagnostic interviews, clinician severity ratings, and behavioral avoidance tests, whereas fears, general anxiety, depression, and behavior problems were assessed with self- and parent report measures. Assessments were completed pretreatment, posttreatment, and at 6 months following treatment. Results showed that both treatment conditions were superior to the wait list control condition and that 1-session exposure treatment was superior to education support treatment on clinician ratings of phobic severity, percentage of participants who were diagnosis free, child ratings of anxiety during the behavioral avoidance test, and treatment satisfaction as reported by the youth and their parents. There were no differences on self-report measures. Treatment effects were maintained at follow-up. Implications of these findings are discussed.