P-Glycoprotein Is More Efficient at Limiting Uptake than Inducing Efflux of Colchicine and Vinblastine in HL-60 Cells

Purpose. To investigate the role of the P-glycoprotein (P-gp) drug efflux pump in the intracellular disposition of colchicine and vinblastine. Methods. Uptake and efflux kinetics were studied in vitro in human lymphocytes and in HL-60 cells with or without the P-gp modulator, verapamil. Results. In human lymphocytes, colchicine was slowly taken up (uptake half-life was 18.9 ± 1.1 hr.) and verapamil increased colchicine uptake by 37%, whereas it did not modify colchicine efflux from cells. In HL-60 cells, colchicine uptake was non-linear and slower than that of vinblastine, the colchicine uptake half-life (11.1 ± 0.5 hr.) being 25-fold longer than that of vinblastine at 25 nM. Verapamil did not significantly modify colchicine uptake half-life, but increased its intracellular accumulation by 23% and that of vinblastine by 81%. Immuno-flow cytometry showed that P-gp expression in HL-60 cells increased significantly from 24 hr. following colchicine or vinblastine exposure. The significant increase in colchicine uptake induced by verapamil at 24 hr. was correlated with this enhanced P-gp expression. The drug efflux half-life was 11.5-fold higher for colchicine (23 ± 0.9 hr) than vinblastine, indicating a much slower elimination of colchicine from cells that could be related to its longer dissociation half-life from the tubulin receptor. Verapamil treatment did not modulate either colchicine or vinblastine efflux kinetics, suggesting that the intracellular drugs are not available to the transmembrane P-gp binding sites. Conclusions. P-gp may not be the main reason for the slowness of colchicine uptake. It may be more efficient at controlling entry of colchicine and vinblastine through the plasma membrane than at mediating their efflux from HL-60 cells.     

Serial Intervals for SARS-CoV-2 Omicron and Delta Variants,Belgium, November 19–December 31, 2021

We investigated the serial interval for SARS-CoV-2 Omicron BA.1 and Delta variants and observed a shorter serial interval for Omicron, suggesting faster transmission. Results indicate a relationship between empirical serial interval and vaccination status for both variants. Further assessment of the causes and extent of Omicron dominance over Delta is warranted.     

Sinonasal pathology in nonallergic asthma and COPD: 'united airway disease' beyond the scope of allergy

Background:  In contrast to the epidemiological and clinical association between allergic rhinitis and asthma, upper airway inflammation is less characterized in patients with nonatopic asthma and virtually unexplored in chronic obstructive pulmonary disease (COPD). Here, sinonasal pathology is studied in patients with allergic asthma, nonallergic asthma and COPD.
Methods:  Ninety patients with stable bronchial disease were included in the study, of which 35 were diagnosed with allergic asthma, 24 with nonallergic asthma and 31 with COPD. Concurrently, 61 control subjects without pulmonary disease were included and matched for age and smoking habits respectively with the asthma and the COPD group. Sinonasal symptoms were evaluated on a visual analogue scale and rhinosinusitis-related impairment of quality of life was assessed with the sino-nasal outcome test-22 (SNOT-22) questionnaire. Nasal mucosal abnormalities were quantified with nasal endoscopy and nasal secretions collected for measuring inflammatory mediators.
Results:  Allergic asthmatics, nonallergic asthmatics and COPD patients reported more nasal symptoms than their respective control subjects, had a higher SNOT-22 score and presented more mucosal abnormalities in the nose. Nasal secretions of both allergic and nonallergic asthmatics contained higher levels of eotaxin, G-CSF, IFN-γ and MCP-1 than controls. Allergic asthmatics had higher nasal IP-10 levels as well. COPD-patients had higher nasal levels of eotaxin, G-CSF and IFN-γ than controls.
Conclusion:  Patients with allergic and nonallergic asthma and COPD show increased nasal symptoms and more nasal inflammation. Hence, our data confirm the 'united airways' concept to be beyond the scope of allergic asthma.     

Modulation of Kupffer cell and peripheral blood monocyte activity by in vivo treatment of rats with all-trans-retinol

Abstract: Previous studies have shown that large doses of vitamin A potentiate chemical-induced liver injury and that the Kupffer cell is directly involved in this potentiation. Therefore, these studies were designed to determine if Kupffer cells isolated from vitamin A treated male Sprague-Dawley rats (75 mg/kg/day for 3–7 days as all- trans-retinol) had altered activity and function. Respiratory activity of Kupffer cells isolated from rats treated with vitamin A for 3 to 7 days markedly increased. Similarly, phagocytic activity was significantly elevated (up to 9-fold) after exposure to vitamin A for 3 to 7 days. Production of reactive oxygen species, measured by luminol-enhanced chemiluminescence of Kupffer cells isolated after 7 days of vitamin A exposure, was significantly higher than that of control cells when stimulated with opsonized zymosan. Also, the release of superoxide anion by individual Kupffer cells isolated from vitamin A treated rats was nearly three times greater than that of control cells. Basal production of tumor necrosis factor-alpha (TNF-α) and prostaglandin E2 (PGE₂) production were significantly elevated in Kupffer cells isolated from rats treated with vitamin A. Lastly, peripheral blood monocytes (PBMC) isolated from rats treated with vitamin A for 7 days had a significantly greater respiratory activity, as well as TNF-α and PGE₂ production, than PBMC isolated from control rats. Our data suggest that large doses of vitamin A enhance both Kupffer cell and PBMC function. Upregulation of the activity by these phagocytic cells may play a role in the vitamin A potentiation of chemical-induced liver injury.     

Rapid confirmation of HIV infection.

OBJECTIVE: To investigate the utility of a prototype rapid confirmatory HIV assay which offers specific results in 5 min and has applications in a variety of important testing situations. METHODS: The performance of the rapid confirmatory assay was assessed with 849 blood samples, including serum, plasma, venipuncture whole blood, and peripheral blood collected via fingerstick. Included were over 700 HIV Western blot (WB)-confirmed antibody positive sera, and others which were classified as negative or indeterminate by WB. The analytic sensitivity of the rapid confirmatory assay was assessed using 13 HIV-1 seroconversion panels, and all results were compared to those of an FDA-licensed WB reference test. RESULTS: The rapid test exhibited 100% concordance with the reference test when testing HIV-1 WB-confirmed positive samples, and 92.3% concordance with samples having WB-inconclusive results. The sensitivity for confirming recent seroconversion was as good, or better than, the FDA-licensed HIV-1 WB in 10/13 panels. The rapid assay performed accurately with whole blood collected from fingerstick, and exhibited excellent precision and reproducibility. CONCLUSION: We conclude that this rapid HIV confirmatory assay, the first of its kind, demonstrates proof of principle for the accurate confirmation of HIV-1 infection and offers important advantages in public health and clinical testing venues.     

Data-driven methods for imputing national-level incidence in global burden of disease studies

Objective

To develop transparent and reproducible methods for imputing missing data on disease incidence at national-level for the year 2005.

Methods

We compared several models for imputing missing country-level incidence rates for two foodborne diseases – congenital toxoplasmosis and aflatoxin-related hepatocellular carcinoma. Missing values were assumed to be missing at random. Predictor variables were selected using least absolute shrinkage and selection operator regression. We compared the predictive performance of naive extrapolation approaches and Bayesian random and mixed-effects regression models. Leave-one-out cross-validation was used to evaluate model accuracy.

Findings

The predictive accuracy of the Bayesian mixed-effects models was significantly better than that of the naive extrapolation method for one of the two disease models. However, Bayesian mixed-effects models produced wider prediction intervals for both data sets.

Conclusion

Several approaches are available for imputing missing data at national level. Strengths of a hierarchical regression approach for this type of task are the ability to derive estimates from other similar countries, transparency, computational efficiency and ease of interpretation. The inclusion of informative covariates may improve model performance, but results should be appraised carefully.