Individual differences in cocaine-induced locomotor activity in rats: behavioral characteristics, cocaine pharmacokinetics, and the dopamine transporter.

Outbred male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor response to acute cocaine. Concomitant measurement of dopamine clearance in these rats revealed that the differential behavioral responses are associated with the magnitude of dopamine transporter (DAT) inhibition by cocaine. Here, we investigated several factors that might contribute to cocaine-induced behavioral variability and its association with differential inhibition of DAT function. In rats classified as LCRs or HCRs after 10 mg/kg cocaine injection, we found no differences in (1) novelty-induced locomotion, (2) cocaine levels in dorsal striatum or nucleus accumbens (NAc), (3) DAT number or affinity in NAc, or (4) DAT affinity for cocaine in NAc. In rats given 20 mg/kg cocaine, behavior was more uniform across individuals, but still warranted separation into LCR/HCR categories. Additionally, we analyzed the stability of the LCR/HCR classification made during the first test with 10 or 20 mg/kg cocaine by retesting rats 7 days later with saline or cocaine (10 or 20 mg/kg). Before injection, HCRs were more active relative to LCRs and to their own behavior on the first test day. Following cocaine, LCRs and HCRs exhibited similar drug-induced changes in locomotion, but there were unique effects that depended on the cocaine dose given on the first and second test days. Our results argue against several likely explanations for individual differences in cocaine-induced behavior and highlight the influence of a single cocaine exposure on subsequent behavioral responses to the drug.     

Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer.

PURPOSE: The human epidermal growth factor receptor (EGFR) plays an oncogenic role in solid cancer, including brain cancer. The present study was designed to prolong survival in mice with intracranial human brain cancer with the weekly i.v. injection of nonviral gene therapy causing RNA interference (RNAi) of EGFR gene expression. EXPERIMENTAL DESIGN: Human U87 gliomas were implanted in the brain of adult scid mice, and weekly i.v. gene therapy was started at day 5 after implantation of 500000 cells. An expression plasmid encoding a short hairpin RNA directed at nucleotides 2529-2557 within the human EGFR mRNA was encapsulated in pegylated immunoliposomes. The pegylated immunoliposome was targeted to brain cancer with 2 receptor-specific monoclonal antibodies (MAb), the murine 83-14 MAb to the human insulin receptor and the rat 8D3 MAb to the mouse transferrin receptor. RESULTS: In cultured glioma cells, the delivery of the RNAi expression plasmid resulted in a 95% suppression of EGFR function, based on measurement of thymidine incorporation or intracellular calcium signaling. Weekly i.v. RNAi gene therapy caused reduced tumor expression of immunoreactive EGFR and an 88% increase in survival time of mice with advanced intracranial brain cancer. CONCLUSIONS: Weekly i.v. nonviral RNAi gene therapy directed against the human EGFR is a new therapeutic approach to silencing oncogenic genes in solid cancers. This is enabled with a nonviral gene transfer technology that delivers liposome-encapsulated plasmid DNA across cellular barriers with receptor-specific targeting ligands.     

Adipose concentrations of organochlorine compounds and breast cancer recurrence in Long Island, New York.

Several studies have measured the association between blood or adipose concentrations of organochlorinated compounds (OCs), such as pesticides and polychlorinated biphenyls (PCBs), and breast cancer. The estrogenic effects of OCs might adversely affect breast cancer recurrence. The participants were 224 women with nonmetastatic breast cancer enrolled in a New York-based case-control study. Supercritical fluid extraction followed by gas chromatography was conducted on adipose surgical specimens to determine OC concentrations. The mean follow-up time from surgery was 3.6 years. Thirty women (13.4%) were diagnosed with a recurrence. The concentration of pesticides and PCBs was correlated with baseline age and body mass index, but not with cancer stage. The highest tertile of total PCB concentration was associated with an increased risk of recurrence [relative risk (RR), 2.9; 95% confidence interval (CI), 1.02-8.2 versus the lowest tertile]. The risk for the highest tertile of the PCB congener Ballschmiter and Zell 118 was 4.0 (95% CI, 1.3-4.9). There was an increased risk for the middle level of the most abundant pesticide, 1,1-dichloro-2,2-di(4-chlorophenyl)ethylene (RR, 2.3; 95% CI, 0.9-5.7), and for beta-hexachlorocyclohexane, but not for their highest levels. Self-reported home termiticide exposure, alcohol consumption (> or = 1 drink/day), and race were not associated with prognosis. The RR for current cigarette smoking at diagnosis was 2.1 (95% CI, 0.9-5.1). In contrast to previous data showing no relationship between OC exposure and risk of breast cancer in these women, adipose PCB concentrations were associated with tumor recurrence. Pesticide levels were not related to recurrence.     

The effect of anticoagulation on antenatal ultrasound findings in pregnant women with thrombophilia.

OBJECTIVE: To assess whether treatment with heparin alters ultrasound findings in pregnant women with inherited thrombophilia. METHODS: This was a retrospective study of a cohort of patients referred for pregnancy complications who were found to have genetic thrombophilia. Ultrasounds were reviewed in treated and untreated pregnancies for the presence of growth restriction, oligohydramnios or abnormal Doppler results. RESULTS: There were a total of 178 pregnancies in 51 patients. The overall percentage of abnormal ultrasounds was significantly greater in the untreated compared with treated pregnancies (52.8% vs. 27.9%; p = 0.024.) Growth restriction and abnormal Doppler results were more common in untreated pregnancies. There was a significantly decreased risk of oligohydramnios with treatment (27.3% vs. 7%; p = 0.03). Overall outcomes were significantly improved with the use of anticoagulation ( p < 0.0001). CONCLUSIONS: Treatment markedly improves ultrasound parameters of growth, fluid and feto-placental blood flow in patients with thrombophilia. The presence of abnormalities despite treatment reinforces the need for close antenatal surveillance.     

Anti‐SARS‐CoV‐2 IgG antibody levels among Thai healthcare providers receiving homologous and heterologous COVID‐19 vaccination regimens

BackgroundWe examined SARS‐CoV‐2 anti‐spike 1 IgG antibody levels following COVID‐19 vaccination (AstraZeneca [AZ], Sinovac [SV], Pfizer‐BioNTech [PZ]) among Thai healthcare providers.MethodsBlood specimens were tested using enzyme‐linked immunosorbent assay. We analyzed seven vaccination regimens: (1) one dose of AZ or SV, (2) two doses of homologous (2AZ, 2SV) or heterologous (1AZ + 1PZ) vaccines, and (3) three doses of heterologous vaccines (2SV + 1AZ, 2SV + 1PZ). Differences in antibody levels were assessed using Kruskal–Wallis statistic, Mann–Whitney test, or Wilcoxon matched‐pairs signed‐rank test. Antibody kinetics were predicted using fractional polynomial regression.ResultsThe 563 participants had median age of 39 years; 92% were female; 74% reported no underlying medical condition. Antibody levels peaked at 22–23 days in both 1AZ and 2SV vaccinees and dropped below assay''s cutoff for positive (35.2 binding antibody units/ml [BAU/ml]) in 55 days among 1AZ vaccinees compared with 117 days among 2SV vaccinees. 1AZ + 1PZ vaccination regimen was highly immunogenic (median 2279 BAU/ml) 1–4 weeks post vaccination. 2SV + 1PZ vaccinees had significantly higher antibody levels than 2SV + 1AZ vaccinees 4 weeks post vaccination (3423 vs. 2105 BAU/ml; p‐value < 0.01), and during weeks 5–8 (3656 vs. 1072 BAU/ml; p‐value < 0.01). Antibodies peaked at 12–15 days in both 2SV + 1PZ and 2SV + 1AZ vaccinees, but those of 2SV + 1AZ declined more rapidly and dropped below assay''s cutoff in 228 days while those of 2SV + 1PZ remained detectable.Conclusions1AZ + 1PZ, 2SV + 1AZ, and 2SV + 1PZ vaccinees had substantial IgG levels, suggesting that these individuals likely mounted sufficient anti‐S1 IgG antibodies for possible protection against SARS‐CoV‐2 infection.     

Papers Please - Predictive Factors of National and International Attitudes Toward Immunity and Vaccination Passports: Online Representative Surveys

BackgroundIn response to the COVID-19 pandemic, countries are introducing digital passports that allow citizens to return to normal activities if they were previously infected with (immunity passport) or vaccinated against (vaccination passport) SARS-CoV-2. To be effective, policy decision-makers must know whether these passports will be widely accepted by the public and under what conditions. This study focuses attention on immunity passports, as these may prove useful in countries both with and without an existing COVID-19 vaccination program; however, our general findings also extend to vaccination passports.ObjectiveWe aimed to assess attitudes toward the introduction of immunity passports in six countries, and determine what social, personal, and contextual factors predicted their support.MethodsWe collected 13,678 participants through online representative sampling across six countries—Australia, Japan, Taiwan, Germany, Spain, and the United Kingdom—during April to May of the 2020 COVID-19 pandemic, and assessed attitudes and support for the introduction of immunity passports.ResultsImmunity passport support was moderate to low, being the highest in Germany (775/1507 participants, 51.43%) and the United Kingdom (759/1484, 51.15%); followed by Taiwan (2841/5989, 47.44%), Australia (963/2086, 46.16%), and Spain (693/1491, 46.48%); and was the lowest in Japan (241/1081, 22.94%). Bayesian generalized linear mixed effects modeling was used to assess predictive factors for immunity passport support across countries. International results showed neoliberal worldviews (odds ratio [OR] 1.17, 95% CI 1.13-1.22), personal concern (OR 1.07, 95% CI 1.00-1.16), perceived virus severity (OR 1.07, 95% CI 1.01-1.14), the fairness of immunity passports (OR 2.51, 95% CI 2.36-2.66), liking immunity passports (OR 2.77, 95% CI 2.61-2.94), and a willingness to become infected to gain an immunity passport (OR 1.6, 95% CI 1.51-1.68) were all predictive factors of immunity passport support. By contrast, gender (woman; OR 0.9, 95% CI 0.82-0.98), immunity passport concern (OR 0.61, 95% CI 0.57-0.65), and risk of harm to society (OR 0.71, 95% CI 0.67-0.76) predicted a decrease in support for immunity passports. Minor differences in predictive factors were found between countries and results were modeled separately to provide national accounts of these data.ConclusionsOur research suggests that support for immunity passports is predicted by the personal benefits and societal risks they confer. These findings generalized across six countries and may also prove informative for the introduction of vaccination passports, helping policymakers to introduce effective COVID-19 passport policies in these six countries and around the world.