Search

Objectives: Tenofovir alafenamide, a prodrug of tenofovir, produces higher PBMC concentrations of tenofovir diphosphate (tenofovir-dp) than tenofovir disoproxil fumarate. To understand tenofovir alafenamide's mucosal tissue distribution and its implications for pre-exposure prophylaxis, we characterized tenofovir-dp in female genital tract (FGT) and lower gastrointestinal (GI) tissues., Methods: Healthy seronegative women were given 5, 10 or 25 mg of tenofovir alafenamide ( n  =   8/group). Each participant provided plasma, PBMC and cervical, vaginal and rectal tissue samples over 14 days. Plasma, cell lysate and tissue homogenate concentrations were analysed by LC-MS/MS. Dose proportionality was declared in plasma and PBMCs if the natural log AUC versus natural log dose regression line 90% CI was within 0.57-1.43. In vitro tenofovir-dp formation was assessed in PBMCs and ectocervical (Ect1/E6E7) and vaginal (VK2/E6E7) cells incubated in 0.5 and 10 μM tenofovir alafenamide or tenofovir. clinicaltrials.gov: NCT02357602., Results: Following single doses of 5, 10 and 25 mg, median (IQR) tenofovir plasma AUC 0-14 days was 52.8 (49.5-59.6), 78.1 (68.2-86.9) and 169.7 (131.2-211.4) ng·h/mL and tenofovir-dp PBMC AUC 0-14 days was 2268 (1519-4090), 4584 (3113-5734) and 9306 (6891-10785) fmol·h/10 6 cells, respectively. Tenofovir was quantifiable in 52% and 92% of FGT and GI tissues, whereas tenofovir-dp was quantifiable in only 5% and 19% of FGT and GI tissues, respectively. Plasma tenofovir and PBMC tenofovir-dp were dose proportional (90% CI = 0.87-1.15 and 0.62-1.02, respectively). In vitro tenofovir-dp was 1.7-17-fold higher in epithelial cells than PBMCs., Conclusions: After tenofovir alafenamide dosing in vivo , tenofovir-dp was unquantifiable in most tissues (91%) although cervical and vaginal epithelial cells efficiently formed tenofovir-dp from tenofovir alafenamide in vitro . These findings warrant further investigation of tenofovir alafenamide's pharmacology., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Model systems that rapidly identify tissue drug concentrations protective of HIV infection could streamline the development of chemoprevention strategies. Tissue models are promising, but limited concentration targets exist, and no systematic comparison to cell models or clinical studies has been performed., Design: We explored the efficacy of maraviroc (MVC) and tenofovir (TFV) for HIV prevention by comparing Emax models from TZM-bl cells to vaginal tissue explants and evaluated their predictive capabilities with a dose-challenge clinical study., Methods: HIV-1JR-CSF was used for viral challenge. Drug efficacy was assessed using a luciferase reporter assay in TZM-bl cells and real-time PCR to quantify spliced RNA in a tissue explant model. Cell and tissue concentrations of MVC, TFV, and the active metabolite tenofovir diphosphate were measured by liquid chromatography with tandem mass spectrometry and used to create Emax models of efficacy. Efficacy after a single oral dose of 600 mg MVC and 600 mg tenofovir disoproxil fumarate was predicted from cell and tissue models and confirmed in a clinical study with viral biopsy challenge postdose., Results: TFV was >10-fold and MVC >1000-fold, more potent in TZM-bl cells compared with vaginal explant tissue. In the dose-challenge study, tissues from 3 of 6 women were protected from HIV infection, which was 49% lower than predicted by TZM-bl data and 36% higher than predicted by tissue explant data., Conclusions: Comparative effective concentration data were generated for TFV and MVC in 3 HIV chemoprophylaxis models. These results provide a framework for future early investigations of antiretroviral efficacy in HIV prevention to optimize dosing strategies in clinical investigations.

Even with the most meticulous planning, and utilizing the most experienced fossil-hunters, fossil prospecting in remote and/or extensive areas can be time-consuming, expensive, logistically challenging, and often hit or miss. While nothing can predict or guarantee with 100% assurance that fossils will be found in any particular location, any procedures or techniques that might increase the odds of success would be a major benefit to the field. Here we describe, and test, one such technique that we feel has great potential for increasing the probability of finding fossiliferous sediments - a relatively simple spectral signature model using the spatial analysis and image classification functions of ArcGIS(®)10 that creates interactive thematic land cover maps that can be used for "remote" fossil prospecting. Our test case is the extensive Eocene sediments of the Uinta Basin, Utah - a fossil prospecting area encompassing ∼1200 square kilometers. Using Landsat 7 ETM+ satellite imagery, we "trained" the spatial analysis and image classification algorithms using the spectral signatures of known fossil localities discovered in the Uinta Basin prior to 2005 and then created interactive probability models highlighting other regions in the Basin having a high probability of containing fossiliferous sediments based on their spectral signatures. A fortuitous "post-hoc" validation of our model presented itself. Our model identified several paleontological "hotspots", regions that, while not producing any fossil localities prior to 2005, had high probabilities of being fossiliferous based on the similarities of their spectral signatures to those of previously known fossil localities. Subsequent fieldwork found fossils in all the regions predicted by the model., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The incorporation of research tools and analytical approaches from the geospatial sciences is a welcome trend for the study of primate and human evolution. The use of remote sensing (RS) imagery and geographic information systems (GIS) allows vertebrate paleontologists, paleoanthropologists, and functional morphologists to study fossil localities, landscapes, and individual specimens in new and innovative ways that recognize and analyze the spatial nature of much paleoanthropological data. Whether one is interested in locating and mapping fossiliferous rock units in the field, creating a searchable and georeferenced database to catalog fossil localities and specimens, or studying the functional morphology of fossil teeth, bones, or artifacts, the new geospatial sciences provide an essential element in modern paleoanthropological inquiry. In this article we review recent successful applications of RS and GIS within paleoanthropology and related fields and argue for the importance of these methods for the study of human evolution in the twenty first century. We argue that the time has come for inclusion of geospatial specialists in all interdisciplinary field research in paleoanthropology, and suggest some promising areas of development and application of the methods of geospatial science to the science of human evolution., (Copyright © 2011 Wiley Periodicals, Inc.)

Michigan water quality standards for public bathing beaches require local health departments to collect and analyze a minimum of three water samples for Escherichia coli during each sampling event. The geometric mean number of E. coli colonies is then compared to the 300 colonies per 100 ml standard to determine compliance. This article compares the results of the currently mandated procedure to a composite sampling method, whereby the three samples are mixed in equal volumes and analyzed once. This effectively replaces the geometric mean of the individual sample results with an arithmetic mean. Although arithmetic means are more affected by outliers, this sensitivity to high concentrations is more health conservative than the geometric mean. During the 2007 sampling season, nine bathing beaches were monitored once each week. Three individual point samples and a composite sample were analyzed for each sampling event. No statistically significant differences in bacteria concentrations were found between composite sample analysis and the arithmetic mean of individual point sample analyses. No violations were detected in the 2007 sampling season, so using historical data, a retrospective analysis was performed on samples gathered at nine bathing beaches in Kalamazoo County, Michigan during the years 2001-2007. The arithmetic mean of the three samples taken at each site served as a surrogate composite sample. The benefits of compositing the three samples were investigated assuming a 2/3 reduction in analytical costs. In the traditional sampling method, three individual samples were obtained and analyzed once in every 3-week period during the summer season, whereas compositing was simulated by taking the arithmetic mean of each week's results. The results of this retrospective cost analysis indicates that ten to 14 violations would have been missed using the less frequent traditional sampling and analysis methodology. Composite sampling is a cost-saving alternative to traditional sampling techniques that can be more protective of public health, particularly when the savings are applied to increased numbers of samples in time or space.

The use of pulsatile perfusion during bypass should create a more physiological milieu and thus attenuate the vasopressin stress response. To determine this, 20 patients scheduled for elective coronary artery bypass operation were studied in two groups. Group 1 had a standard nonpulsatile perfusion, and in Group 2 a pulsatile pump was used. Measurements were made before and after anesthesia, after surgical incision, and at 15 and 30 minutes during and after cardiopulmonary bypass. In both groups, vasopressin levels were significantly elevated after sternotomy (4.5 +/- 1.5 to 37 +/- 10 pg/ml in Group 1 and 3.1 +/- 1.2 to 33 +/- 9 pg/ml in Group 2, p less than 0.05) and during bypass (198 +/- 19 pg/ml in Group 1 and 113 +/- 16 pg/ml in Group 2) but were higher in Group 1 (p less than 0.05). With comparable perfusion pressures in both groups, Group 2 required higher flow (4.2 +/- 0.2 versus 3.5 +/- 0.3 L/min, p less than 0.05) and had lower resistance (1,351 +/- 182 versus 1,841 +/- 229 dynes sec cm-5, p less than 0.05) and higher urine Na+ (123 +/- 5 versus 101 +/- 8 mEq/L, p less than 0.05). These data demonstrate that pulsatile flow can significantly attentuate the vasopressin stress response to bypass. Since vasopressin, at these concentrations, is a potent vasoconstrictor and is capable of producing a Na+ diuresis, this may partially explain the higher flow requirements and the decrease in Na+ excretion.

The effect of pulsatile flow on plasma vasopressin levels during cardiopulmonary bypass (CPB) was studied in 20 patients undergoing open valve replacement. Routine bypass was used in 10 patients and the AVCO pulsatile bypass pump was utilized in the other 10. In Group I (nonpulsatile) during CPB, the vasopressin level was markedly elevated (3.1 +/- 2 to 80 +/- 22 pg/ml) as was urine flow (0.6 +/- 0.2 to 5.9 +/- 2 ml/min) and urine Na+ concentration (69 +/- 19 to 116 +/- 7 mEq/L). In Group II (pulsatile) during CPB, the vasopressin level (3.8 +/- 3 to 54 +/- 14 pg/ml), urine flow (0.6 +/- 0.1 to 16.2 +/- 4.8 ml/min), and urine Na+ concentrations (61 +/- 13 to 97 +/- 10 mEq/L) were also elevated. The rise in vasopressin and urine Na+ was less in the pulsatile group (p less than 0.05) whereas the urine flow was higher (p less than 0.05). To maintain comparable blood pressure, the pulsatile flow group required significantly higher flows (4.5 +/- 0.2 compared to 3.8 +/- 0.2; p less than 0.05). These data suggest that CPB produces a marked vasopressin stress response which is beyond the physiological range for an antidiuretic effect on the kidney. At these levels vasopressin can exert a vasopressor effect to maintain resistance and affect renal blood flow, as well as producing an Na+ diuresis. The addition of pulsatile flow creates a more physiological situation attenuating the vasopressin response and producing a decrease in systemic resistance and a less pronounced Na+ diuresis.