Evaluating a Simple Approach to Identify Adults Meeting the 2018 AHA/ACC Cholesterol Guideline Definition of Very High Risk for Atherosclerotic Cardiovascular Disease.

PURPOSE: The 2018 American Heart Association/American College of Cardiology (AHA/ACC) cholesterol guideline defines very high atherosclerotic cardiovascular disease (ASCVD) risk as a history of ≥ 2 major ASCVD events or 1 major ASCVD event and multiple high-risk conditions. We tested if a simplified approach, having a history of a major ASCVD event, would identify a high proportion of patients that meet the 2018 AHA/ACC cholesterol guideline criteria for very high risk. METHODS: We analyzed data from US adults with health insurance in the MarketScan database who had experienced an acute coronary syndrome in the past year (recent ACS, n = 3626), a myocardial infarction (MI) other than a recent ACS (n = 7572), an ischemic stroke (n = 3551), or symptomatic peripheral artery disease (PAD, n = 5919). Patients were followed from January 1, 2016, through December 31, 2017, for recurrent ASCVD events. RESULTS: Among 16,344 patients with a history of a major ASCVD event, 94.0% met the 2018 AHA/ACC cholesterol guideline definition for very high risk including 92.9%, 96.5%, 93.1%, and 96.2% with a recent ACS, history of MI, history of stroke, and symptomatic PAD, respectively. The incidence of ASCVD events per 1000 person-years was 50.4 (95% CI: 47.6-53.3) among all patients with a history of a major ASCVD event versus 53.1 (95% CI: 50.1-56.1) among patients who met the 2018 AHA/ACC cholesterol guideline definition of very high risk. CONCLUSION: The vast majority of patients with a recent ACS, history of MI, ischemic stroke, or symptomatic PAD meet the 2018 AHA/ACC cholesterol guideline definition of very high risk.

A phase II study of efficacy, toxicity, and the potential impact of genomic alterations on response to eribulin mesylate in combination with trastuzumab and pertuzumab in women with human epidermal growth factor receptor 2 (HER2)+ metastatic breast cancer.

PURPOSE: There are limited data on trastuzumab-pertuzumab (HP)-based treatments beyond the first-line, HER2+ metastatic breast cancer (MBC) setting. We conducted a phase II study of eribulin mesylate, which extends survival in MBC, with HP in patients with previously treated HER2+ MBC to evaluate efficacy, toxicity, and genomic alterations driving therapeutic response. METHODS: After a run-in phase for eribulin dosing, two cohorts were enrolled (Cohort A-no prior pertuzumab; Cohort B-prior pertuzumab). All patients received eribulin 1.4 mg/m2 on days 1, 8 with standard-dose HP on day 1 (21-day cycles). The primary endpoint was objective response rate (ORR). Genomic characterization via whole exome sequencing (WES) was completed on tumor DNA and matched germline DNA from 19 patients. RESULTS: The six-patient run-in established a dose of eribulin 1.4 mg/m2 with HP. Cohorts A and B enrolled 17 and 7 patients, respectively. Accrual stopped early due to an evolving treatment landscape and slow enrollment. The ORR was 26.3% (95% Confidence Interval [CI] 9.2-51.2%) in Cohort A and 0% in Cohort B (95% CI 0-41.0%). WES revealed more frequent alterations in TP53 (p < 0.05, q > 0.05) in patients without clinical benefit (disease control for < 24 weeks) which was not significant after multiple hypothesis correction. CONCLUSION: Eribulin-HP had manageable toxicity and modest clinical activity in patients without prior pertuzumab exposure. This study provides a preliminary landscape of somatic alterations in this patient cohort. Our data add to the literature on how genomic alterations may predict for therapy response/resistance, as we work to individualize choices in a quickly evolving HER2+ MBC treatment landscape. TRIAL REGISTRATION: www.clinicaltrials.gov , NCT01912963. Registered 24 July 2013.

Low-Density Lipoprotein Cholesterol Testing Following Myocardial Infarction Hospitalization Among Medicare Beneficiaries.

Background: Low-density lipoprotein cholesterol (LDL-C) is used to guide lipid-lowering therapy after a myocardial infarction (MI). Lack of LDL-C testing represents a missed opportunity for optimizing therapy and reducing cardiovascular risk. Objectives: The purpose of this study was to estimate the proportion of Medicare beneficiaries who had their LDL-C measured within 90 days following MI hospital discharge. Methods: We conducted a retrospective cohort study of Medicare beneficiaries ≥66 years of age with an MI hospitalization between 2016 and 2020. The primary analysis used data from all beneficiaries with fee-for-service coverage and pharmacy benefits (532,767 MI hospitalizations). In secondary analyses, we used data from a 5% random sample of beneficiaries with fee-for-service coverage without pharmacy benefits (10,394 MI hospitalizations), and from beneficiaries with Medicare Advantage (176,268 MI hospitalizations). The proportion of beneficiaries who had their LDL-C measured following MI hospital discharge was estimated accounting for the competing risk of death. Results: In the primary analysis (mean age 76.9 years, 84.4% non-Hispanic White), 29.9% of beneficiaries had their LDL-C measured within 90 days following MI hospital discharge. Among Hispanic, Asian, non-Hispanic White, and non-Hispanic Black beneficiaries, the 90-day postdischarge LDL-C testing was 33.8%, 32.5%, 30.0%, and 26.0%, respectively. Postdischarge LDL-C testing within 90 days was highest in the Middle Atlantic (36.4%) and lowest in the West North Central (23.4%) U.S. regions. In secondary analyses, the 90-day postdischarge LDL-C testing was 26.9% among beneficiaries with fee-for-service coverage without pharmacy benefits, and 28.6% among beneficiaries with Medicare Advantage coverage. Conclusions: LDL-C testing following MI hospital discharge among Medicare beneficiaries was low.

Cell states and neighborhoods in distinct clinical stages of primary and metastatic esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a highly lethal cancer of the upper gastrointestinal tract with rising incidence in western populations. To decipher EAC disease progression and therapeutic response, we performed multiomic analyses of a cohort of primary and metastatic EAC tumors, incorporating single-nuclei transcriptomic and chromatin accessibility sequencing, along with spatial profiling. We identified tumor microenvironmental features previously described to associate with therapy response. We identified five malignant cell programs, including undifferentiated, intermediate, differentiated, epithelial-to-mesenchymal transition, and cycling programs, which were associated with differential epigenetic plasticity and clinical outcomes, and for which we inferred candidate transcription factor regulons. Furthermore, we revealed diverse spatial localizations of malignant cells expressing their associated transcriptional programs and predicted their significant interactions with microenvironmental cell types. We validated our findings in three external single-cell RNA-seq and three bulk RNA-seq studies. Altogether, our findings advance the understanding of EAC heterogeneity, disease progression, and therapeutic response.

Intertumoral lineage diversity and immunosuppressive transcriptional programs in well-differentiated gastroenteropancreatic neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare cancers that most often arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic (GEP)-NET growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we investigated the single-cell transcriptomes of tumor and immune cells from patients with gastroenteropancreatic NETs. Malignant GEP-NET cells expressed genes and regulons associated with normal, gastrointestinal endocrine cell differentiation, and fate determination stages. Tumor and lymphoid compartments sparsely expressed immunosuppressive targets commonly investigated in clinical trials, such as the programmed cell death protein-1/programmed death ligand-1 axis. However, infiltrating myeloid cell types within both primary and metastatic GEP-NETs were enriched for genes encoding other immune checkpoints, including VSIR (VISTA), HAVCR2 (TIM3), LGALS9 (Gal-9), and SIGLEC10. Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics.

Enhanced inhibition of Listeria monocytogenes by a combination of cold pressed terpeneless Valencia orange oil and antibiotics.

This study was designed to evaluate the ability of cold pressed terpeneless Valencia orange oil (CPTVO) to enhance the effectiveness of antibiotics against 10 strains of Listeria monocytogenes. Disc diffusion assays were performed to determine the effects of CPTVO and two antibiotics with different mechanisms of action (i.e., penicillin and chloramphenicol) individually and in combination with CPTVO. CPTVO alone produced zones ranging from 16.5 to 19.9 mm. Penicillin at 2 or 10 units produced zones ranging from <6 to 13.4 mm, and from 16 to 19.5 mm, respectively. Chloramphenicol at 5 or 30 µg had zones ranging from <6 to 6.9 mm, and from 10.8 to 15.9 mm, respectively. Penicillin (2 and 10 units) plus CPTVO produced zones ranging from 20.2 to 25.3 mm, and from 21.9 to 28 mm, respectively. Chloramphenicol (5 or 30 µg) plus CPTVO produced zones of from 20.1 to 26.6 mm, and from 19.5 to 23.9 mm, respectively. In conclusion, the combination of antibiotics with CPTVO increases their ability to inhibit L. monocytogenes.

Activation of Tumor-Cell STING Primes NK-Cell Therapy.

Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA sequencing of explants treated with a STING agonist, we observed CXCR3 chemokine activation primarily in tumor cells and cancer-associated fibroblasts, as well as T-cell cytotoxicity. In contrast, primary natural killer (NK) cells resisted STING agonist-induced cytotoxicity. STING agonists enhanced migration and killing of NK cells and mesothelin-targeted chimeric antigen receptor (CAR)-NK cells, improving therapeutic activity in patient-derived organotypic tumor spheroids. These studies reveal the fundamental importance of using human tumor samples to assess innate and cellular immune therapies. By functionally profiling mesothelioma tumor explants with elevated STING expression in tumor cells, we uncovered distinct consequences of STING agonist treatment in humans that support testing combining STING agonists with NK and CAR-NK cell therapies.

Alcohol effects on simulated driving in frequent and infrequent binge drinkers.

OBJECTIVE: Compared with non­bingers, binge drinkers are more likely to drive while intoxicated. The extent to which binge frequency impacts confidence in driving and subsequent driving impairment is unknown. This study compared the effects of an experimenter­delivered alcohol binge on subjective impairment and simulated driving ability in female high­frequency and low­frequency bingers. METHODS: Female drinkers were assigned to high­frequency (n = 30) or low­frequency (n = 30) binge groups based on their Alcohol Use Questionnaire responses. At 30­min intervals within a 2­h period, participants received either a placebo drink (n = 15 per group) or a 0.2 g/kg dose of alcohol (n = 15 per group; cumulative dose 0.8 g/kg). Self­reported impairment, driving confidence, and simulated driving were then measured. RESULTS: Self­reported confidence in driving was significantly lower after alcohol than after placebo in low­frequency but not highfrequency bingers. Self­reported impairment and collisions during simulated driving were significantly greater after alcohol than after placebo in both low­frequency and high­frequency bingers. CONCLUSIONS: The impairing effects of a single alcohol binge on driving ability in women are not influenced by binge frequency. However, high binge frequency may be associated with a less cautious approach to post­binge driving.

Response inhibition impairments predict alcohol-induced sedation.

AIMS: The aim of this study was to probe the relationship between the subjective effects of alcohol and impulsive behavior in social drinkers. METHODS: Fifty social drinkers performed a response-inhibition task before consuming alcohol. A 0.8-g/kg dose of alcohol was administered in a binge-like fashion (0.2 g/kg every 30 min) to the participants over a 2-h time period. Participants then completed questionnaires measuring stimulation, sedation and mood following consumption of alcohol. Linear regression analyses were performed by examining the relationship between performance on the response inhibition impulsivity task and subjective responses to alcohol (i.e. stimulation, sedation and arousal). RESULTS: There was a significant positive relationship found between impulsive responding and self-reported sedation following alcohol consumption. Additionally, there was a significant negative relationship between behavioral impulsivity and self-reported stimulation and arousal following alcohol consumption. CONCLUSION: These results suggest that higher levels of impulsivity are associated with experiencing greater sedating than stimulating effects of alcohol. Individuals with high levels of impulsivity may be less sensitive to the stimulating effects of a specified dose of alcohol, which could lead to these individuals consuming more alcohol to experience the stimulating effects of alcohol.

Effectiveness of Blood Lipid Management in Patients With Peripheral Artery Disease.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is associated with heightened risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in peripheral artery disease (PAD). Lipid-lowering therapies (LLT) that reduce LDL-C decrease this risk. OBJECTIVES: The authors examined LLT use and actual achieved LDL-C in PAD. METHODS: PAD patients in MarketScan from 2014 to 2018 were identified. Outcomes included LLT use, defined as high-intensity (HI) (high-intensity statin, statin plus ezetimibe, or PCSK9 inhibitor), low-intensity (any other lipid regimen), or no therapy, and follow-up LDL-C. Factors associated with LDL-C <70 mg/dl were identified with multivariable logistic regression. RESULTS: Among 250,103 PAD patients, 20.5% and 39.5% were treated at baseline with HI and low-intensity LLT, respectively; 40.0% were on no LLT. Over a 15-month median follow-up period, HI LLT use increased by 1.5%. Among 18,747 patients with LDL-C data, at baseline, 25.1% were on HI LLT, median LDL-C was 91 mg/dl, and 24.5% had LDL-C <70 mg/dl. Within the HI LLT subgroup, median LDL-C was 81 mg/dl, and 64% had LDL-C ≥70 mg/dl. At follow-up, HI LLT use increased by 3.7%, median LDL-C decreased by 4.0 mg/dl, and an additional 4.1% of patients had LDL-C <70 mg/dl. HI LLT use was greater after follow-up MACE (55.0%) or MALE (41.0%) versus no ischemic event (26.1%). After MACE or MALE, LDL-C was <70 mg/dl in 41.5% and 36.1% of patients, respectively, versus 27.1% in those without an event. Factors associated with follow-up LDL-C <70 mg/dl included smoking, hypertension, diabetes, prior lower extremity revascularization, and prior myocardial infarction but not prior acute or critical limb ischemia. CONCLUSIONS: In PAD, LLT use is suboptimal, LDL-C remains elevated, and LLT intensity is a poor surrogate for achieved LDL-C. Less aggressive lipid management was observed in PAD versus cardiovascular disease, highlighting missed opportunities for implementation of proven therapies in PAD.

Clinical Efficacy and Molecular Response Correlates of the WEE1 Inhibitor Adavosertib Combined with Cisplatin in Patients with Metastatic Triple-Negative Breast Cancer.

PURPOSE: We report results from a phase II study assessing the efficacy of the WEE1 inhibitor adavosertib with cisplatin in metastatic triple-negative breast cancer (mTNBC). PATIENTS AND METHODS: Patients with mTNBC treated with 0-1 prior lines of chemotherapy received cisplatin 75 mg/m2 i.v. followed 21 days later by cisplatin plus adavosertib 200 mg oral twice daily for five doses every 21 days. The study had 90% power to detect the difference between null (20%) and alternative (40%) objective response rates (ORR) with a one-sided type I error of 0.1: an ORR >30% was predefined as making the regimen worthy of further study. RNA sequencing and multiplex cyclic immunofluorescence on pre- and post-adavosertib tumor biopsies, as well as targeted next-generation sequencing on archival tissue, were correlated with clinical benefit, defined as stable disease ≥6 months or complete or partial response. RESULTS: A total of 34 patients initiated protocol therapy; median age was 56 years, 2 patients (6%) had BRCA2 mutations, and 14 (41%) had one prior chemotherapy. ORR was 26% [95% confidence interval (CI), 13-44], and median progression-free survival was 4.9 months (95% CI, 2.3-5.7). Treatment-related grade 3-5 adverse events occurred in 53% of patients, most commonly diarrhea in 21%. One death occurred because of sepsis, possibly related to study therapy. Tumors from patients with clinical benefit demonstrated enriched immune gene expression and T-cell infiltration. CONCLUSIONS: Among patients with mTNBC treated with 0-1 prior lines, adavosertib combined with cisplatin missed the prespecified ORR cutoff of >30%. The finding of immune-infiltrated tumors in patients with clinical benefit warrants validation.

Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer.

Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59-1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.

Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma.

Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells, we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB.

Brain activity associated with social exclusion overlaps with drug-related frontal-striatal circuitry in cocaine users: A pilot study.

BACKGROUND: Exposure to various types of stress can elevate craving for cocaine and hasten relapse among substance dependent individuals. This investigation evaluated the effects of social exclusion on brain activity in cocaine dependent individuals. METHOD: Forty three individuals (18 crack-cocaine users, 25 controls) were recruited from the community to participate in functional neuroimaging study in which they performed a simulated 3 person ball-tossing game (Cyberball). Each participant was told that the other 2 players were in nearby MRI scanners. Task blocks included: Inclusion (likelihood of our participant receiving the ball = 50%), Exclusion (likelihood gradually decreases to 0%), and Rest. Self-worth variables (e.g self-esteem, locus of control) were measured before and after the ball-tossing game. General linear model-based statistics were used to measure the brain response to inclusion and exclusion within and between the groups with respect to rest. RESULTS: Relative to controls, cocaine users had significantly more activity during Exclusion versus Inclusion in 3 areas: the right medial frontal gyrus (Brodmann Area 9,10), left ventral lateral frontal gyrus (Brodmann Area 10,47) and right caudate. This was driven by a higher response to social exclusion in the cocaine users. There was no difference between groups in the brain reactivity to social inclusion. CONCLUSION: Cocaine dependent individuals have an amplified brain response to social exclusion stress in cortical regions associated with emotional regulation, arousal, craving and perception of physical pain. These data suggest that there may be a neurological basis for the well-established relationship between social stress and addiction.

Ischemic Event Rates in Very-High-Risk Adults.

BACKGROUND: The 2018 American Heart Association/American College of Cardiology (AHA/ACC) cholesterol guideline includes recommendations for intensive lipid-lowering therapy in patients at very high risk for atherosclerotic cardiovascular disease (ASCVD) events. OBJECTIVES: This study sought to estimate event rates among adults with a history of ASCVD who met and did not meet the definition of very high risk in the 2018 AHA/ACC cholesterol guideline. METHODS: Data from U.S. adults with health insurance in the MarketScan database who had a history of ASCVD on January 1, 2016 (n = 27,775) were analyzed. Very high risk for ASCVD events was defined as a history of ≥2 major ASCVD events or 1 event and ≥2 high-risk conditions. Patients were followed through December 31, 2017, for ASCVD events, including myocardial infarction, ischemic stroke, and major adverse limb events. RESULTS: Overall, 15,366 patients (55.3%) with ASCVD met the definition of very high risk. Among patients with and without very high risk, the ASCVD event rate per 1,000 person-years was 53.1 (95% confidence interval [CI]: 50.1 to 56.1) and 17.0 (95% CI: 15.2 to 18.9), respectively. Among patients with ≥2 major ASCVD events and with 1 event and ≥2 high-risk conditions, the ASCVD event rate per 1,000 person-years was 89.8 (95% CI: 82.2 to 98.0) and 41.3 (95% CI: 38.3 to 44.4), respectively. The age- and sex-adjusted hazard ratios for ASCVD events among patients with very high risk, overall, with ≥2 major ASCVD events and with 1 event and ≥2 high-risk conditions versus those without very high risk were 2.98 (95% CI: 2.63 to 3.37), 4.89 (95% CI: 4.22 to 5.66), and 2.33 (95% CI: 2.04 to 2.66), respectively. CONCLUSIONS: The 2018 AHA/ACC cholesterol guideline directs intensive lipid-lowering therapy to adults with a very high ASCVD event rate.

Teenagers do not always lie: characteristics and correspondence of telephone and in-person reports of adolescent drug use.

Because of the widespread use of drugs by adolescents, there is demand for scientific rigor in sampling and accuracy in methods for ascertaining drug use patterns. The present study: (1) characterized adolescents who responded to advertisements for marijuana users; (2) compared rates of drug use reported on the telephone versus an on-site interview; and (3) examined drug use patterns as a function of parental awareness of drug use. Adolescents, identifying themselves as marijuana users during telephone interviews, reported more use of other drugs than those denying marijuana use. There was a high degree of correspondence between telephone and on-site interviews for all drugs except alcohol, which was reported at a higher rate on-site. Of those reporting marijuana use in the past week, 69% tested positive for marijuana in their urine-drug screens. Finally, marijuana and alcohol use patterns were higher among adolescents whose parents were aware of drug use than those whose parents indicated that their adolescent did not use marijuana. These results indicate that adolescents are willing to self-identify as marijuana users and report drug and alcohol use during telephone interviews. Additionally, parents appear to become more aware of their adolescent's drug use with increased frequency of use.

Discriminative stimulus effects of 5.6 mg/kg pregnanolone in DBA/2J and C57BL/6J inbred mice.

Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as gamma-aminobutyric acid(A) (GABA(A)). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. A previous study examining the discriminative stimulus effects of 10 mg/kg pregnanolone in DBA/2J and C57BL/6J mice showed pregnanolone's discriminative stimulus to be mediated primarily through GABA(A) positive modulation. This study examined the discriminative stimulus effects of a lower training dose (5.6 mg/kg) of pregnanolone in DBA/2J and C57BL/5J mice. Twelve male DBA/2J mice and 12 male C57BL/6J mice were trained to discriminate 5.6 mg/kg pregnanolone. GABA(A)-receptor positive modulators, neuroactive steroids, NMDA receptor antagonists, and 5-HT(3) receptor agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for pregnanolone. In the DBA/2J mice, NMDA receptor antagonists showed generalization to the discriminative stimulus cues of pregnanolone, an effect not seen in the C57BL/6J mice. 5-HT(3) receptor agonists and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either strain. AlloTHDOC and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest GABA(A)-receptor positive modulation as the predominant receptor mechanism mediating the discriminative stimulus effects of pregnanolone. NMDA receptor antagonism was suggested in the DBA/2J mice and may represent a heterogenous cue produced by the lower training dose of pregnanolone.

Characterization of dopamine D1 and D2 receptor function in socially housed cynomolgus monkeys self-administering cocaine.

RATIONALE: Social rank has been shown to influence dopamine (DA) D(2) receptor function and vulnerability to cocaine self-administration in cynomolgus monkeys. The present studies were designed to extend these findings to maintenance of cocaine reinforcement and to DA D(1) receptors. OBJECTIVE: Examine the effects of a high-efficacy D(1) agonist on an unconditioned behavior (eyeblinking) and a low-efficacy D(1) agonist on cocaine self-administration, as well as the effects of cocaine exposure on D(2) receptor function across social ranks, as determined by positron emission tomography (PET). METHODS: Effects of the high-efficacy D(1) agonist SKF 81297 and cocaine (0.3-3.0 mg/kg) on spontaneous blinking were characterized in eight monkeys during 15-min observation periods. Next, the ability of the low-efficacy D(1) agonist SKF 38393 (0.1-17 mg/kg) to decrease cocaine self-administration (0.003-0.1 mg/kg per injection, IV) was assessed in 11 monkeys responding under a fixed-ratio 50 schedule. Finally, D(2) receptor levels in the caudate and putamen were assessed in nineteen monkeys using PET. RESULTS: SKF 81297, but not cocaine, significantly increased blinking in all monkeys, with slightly greater potency in dominant monkeys. SKF 38393 dose-dependently decreased cocaine-maintained response rates with similar behavioral potency and efficacy across social rank. After an extensive cocaine self-administration history, D(2) receptor levels did not differ across social ranks. CONCLUSIONS: These results suggest that D(1) receptor function is not substantially influenced by social rank in monkeys from well-established social groups. While an earlier study showed that dominant monkeys had higher D(2) receptor levels and were less sensitive to the reinforcing effects of cocaine during initial exposure, the present findings indicate that long-term cocaine use changed D(2) receptor levels such that D(2) receptor function and cocaine reinforcement were not different between social ranks. These findings suggest that cocaine exposure attenuated the impact of social housing on DA receptor function.

Chronic conditions: results of the Medicare Health Outcomes Survey, 1998-2000.

This research examines the predictors of 2-year declines in physical and mental health for beneficiaries surveyed in the Medicare Health Outcomes Survey (HOS). Regression results indicate that age, arthritis of the hip/knee, sciatica, and pulmonary diseases, comorbidity at baseline, and increased comorbidity between baseline and followup were predictors of decline in physical health; however, these account for very small amounts of variance. The number of newly diagnosed chronic conditions and depression predicted decline in mental health. Beneficiaries deceased at followup were of lower socioeconomic status, and had lower physical and mental health scores than the analytic sample.