Comparison of Blood and Brain Mercury Levels in Infant Monkeys Exposed to Methylmercury or Vaccines Containing Thimerosal

Thimerosal is a preservative that has been used in manufacturing vaccines since the 1930s. Reports have indicated that infants can receive ethylmercury (in the form of thimerosal) at or above the U.S. Environmental Protection Agency guidelines for methylmercury exposure, depending on the exact vaccinations, schedule, and size of the infant. In this study we compared the systemic disposition and brain distribution of total and inorganic mercury in infant monkeys after thimerosal exposure with those exposed to MeHg. Monkeys were exposed to MeHg (via oral gavage) or vaccines containing thimerosal (via intramuscular injection) at birth and 1, 2, and 3 weeks of age. Total blood Hg levels were determined 2, 4, and 7 days after each exposure. Total and inorganic brain Hg levels were assessed 2, 4, 7, or 28 days after the last exposure. The initial and terminal half-life of Hg in blood after thimerosal exposure was 2.1 and 8.6 days, respectively, which are significantly shorter than the elimination half-life of Hg after MeHg exposure at 21.5 days. Brain concentrations of total Hg were significantly lower by approximately 3-fold for the thimerosal-exposed monkeys when compared with the MeHg infants, whereas the average brain-to-blood concentration ratio was slightly higher for the thimerosal-exposed monkeys (3.5 ± 0.5 vs. 2.5 ± 0.3). A higher percentage of the total Hg in the brain was in the form of inorganic Hg for the thimerosal-exposed monkeys (34% vs. 7%). The results indicate that MeHg is not a suitable reference for risk assessment from exposure to thimerosal-derived Hg. Knowledge of the toxicokinetics and developmental toxicity of thimerosal is needed to afford a meaningful assessment of the developmental effects of thimerosal-containing vaccines

A reversible clearance model for the enterohepatic circulation of drug and conjugate metabolite pair.

ABSTRACT: A

Coenzyme Q10 dose-escalation study in hemodialysis patients: safety, tolerability, and effect on oxidative stress.

BackgroundCoenzyme Q10 (CoQ10) supplementation improves mitochondrial coupling of respiration to oxidative phosphorylation, decreases superoxide production in endothelial cells, and may improve functional cardiac capacity in patients with congestive heart failure. There are no studies evaluating the safety, tolerability and efficacy of varying doses of CoQ10 in chronic hemodialysis patients, a population subject to increased oxidative stress.MethodsWe performed a dose escalation study to test the hypothesis that CoQ10 therapy is safe, well-tolerated, and improves biomarkers of oxidative stress in patients receiving hemodialysis therapy. Plasma concentrations of F2-isoprostanes and isofurans were measured to assess systemic oxidative stress and plasma CoQ10 concentrations were measured to determine dose, concentration and response relationships.ResultsFifteen of the 20 subjects completed the entire dose escalation sequence. Mean CoQ10 levels increased in a linear fashion from 704 ± 286 ng/mL at baseline to 4033 ± 1637 ng/mL, and plasma isofuran concentrations decreased from 141 ± 67.5 pg/mL at baseline to 72.2 ± 37.5 pg/mL at the completion of the study (P = 0.003 vs. baseline and P < 0.001 for the effect of dose escalation on isofurans). Plasma F2-isoprostane concentrations did not change during the study.ConclusionsCoQ10 supplementation at doses as high as 1800 mg per day was safe in all subjects and well-tolerated in most. Short-term daily CoQ10 supplementation decreased plasma isofuran concentrations in a dose dependent manner. CoQ10 supplementation may improve mitochondrial function and decrease oxidative stress in patients receiving hemodialysis.Trial registrationThis clinical trial was registered on clinicaltrials.gov [NCT00908297] on May 21, 2009

Cluster Perturbation Theory for Hubbard models

Cluster perturbation theory is a technique for calculating the spectral weight of Hubbard models of strongly correlated electrons, which combines exact diagonalizations on small clusters with strong-coupling perturbation theory at leading order. It is exact in both the strong- and weak-coupling limits and provides a good approximation to the spectral function at any wavevector. Following the paper by S\'en\'echal et al. (Phys. Rev. Lett. {\bf 84}, 522 (2000)), we provide a more complete description and derivation of the method. We illustrate some of its capabilities, in particular regarding the effect of doping, the calculation of ground state energy and double occupancy, the disappearance of the Fermi surface in the $t-t'$ Hubbard model, and so on. The method is applicable to any model with on-site repulsion only.Comment: 11 pages, 10 figures (RevTeX 4

Aspirin use and knowledge in the community: a population- and health facility based survey for measuring local health system performance

BACKGROUND: Little is known about the relationship between cardiovascular risk, disease and actual use of aspirin in the community. METHODS: The Measuring Disparities in Chronic Conditions (MDCC) study is a community and health facility-based survey designed to track disparities in the delivery of health interventions for common chronic diseases. MDCC includes a survey instrument designed to collect detailed information about aspirin use. In King County, WA between 2011 and 2012, we surveyed 4633 white, African American, or Hispanic adults (45% home address-based sample, 55% health facility sample). We examined self-reported counseling on, frequency of use and risks of aspirin for all respondents. For a subgroup free of CAD or cerebral infarction that underwent physical examination, we measured 10-year coronary heart disease risk and blood salicylate concentration. RESULTS: Two in five respondents reported using aspirin routinely while one in five with a history of CAD or cerebral infarction and without contraindication did not report routine use of aspirin. Women with these conditions used less aspirin than men (65.0% vs. 76.5%) and reported more health problems that would make aspirin unsafe (29.4% vs. 21.2%). In a subgroup undergoing phlebotomy a third of respondents with low cardiovascular risk used aspirin routinely and only 4.6% of all aspirin users had no detectable salicylate in their blood. CONCLUSIONS: In this large urban county where health care delivery should be of high quality, there is insufficient aspirin use among those with high cardiovascular risk or disease and routine aspirin use by many at low risk. Further efforts are needed to promote shared-decision making between patients and clinicians as well as inform the public about appropriate use of routine aspirin to reduce the burden of atherosclerotic vascular disease

pre-clinical assessment of pharmacological and molecular properties

SARS-CoV-2, the cause of the COVID-19 pandemic, exploits host cell proteins for viral entry into human lung cells. One of them, the protease TMPRSS2, is required to activate the viral spike protein (S). Even though two inhibitors, camostat and nafamostat, are known to inhibit TMPRSS2 and block cell entry of SARS-CoV-2, finding further potent therapeutic options is still an important task. In this study, we report that a late-stage drug candidate, otamixaban, inhibits SARS-CoV-2 cell entry. We show that otamixaban suppresses TMPRSS2 activity and SARS-CoV-2 infection of a human lung cell line, although with lower potency than camostat or nafamostat. In contrast, otamixaban inhibits SARS-CoV-2 infection of precision cut lung slices with the same potency as camostat. Furthermore, we report that otamixaban's potency can be significantly enhanced by (sub-) nanomolar nafamostat or camostat supplementation. Dominant molecular TMPRSS2-otamixaban interactions are assessed by extensive 109 μs of atomistic molecular dynamics simulations. Our findings suggest that combinations of otamixaban with supplemental camostat or nafamostat are a promising option for the treatment of COVID-19

Transfer of molecular recognition information from DNA nanostructures to gold nanoparticles

DNA nanotechnology offers unparalleled precision and programmability for the bottom-up organization of materials. This approach relies on pre-assembling a DNA scaffold, typically containing hundreds of different strands, and using it to position functional components. A particularly attractive strategy is to employ DNA nanostructures not as permanent scaffolds, but as transient, reusable templates to transfer essential information to other materials. To our knowledge, this approach, akin to top-down lithography, has not been examined. Here we report a molecular printing strategy that chemically transfers a discrete pattern of DNA strands from a three-dimensional DNA structure to a gold nanoparticle. We show that the particles inherit the DNA sequence configuration encoded in the parent template with high fidelity. This provides control over the number of DNA strands and their relative placement, directionality and sequence asymmetry. Importantly, the nanoparticles produced exhibit the site-specific addressability of DNA nanostructures, and are promising components for energy, information and biomedical applications

SN 2019ehk: A Double-peaked Ca-rich Transient with Luminous X-Ray Emission and Shock-ionized Spectral Features

We present panchromatic observations and modeling of the Calcium-rich supernova (SN) 2019ehk in the star-forming galaxy M100 (d ≈ 16.2 Mpc) starting 10 hr after explosion and continuing for ~300 days. SN 2019ehk shows a double-peaked optical light curve peaking at t = 3 and 15 days. The first peak is coincident with luminous, rapidly decaying Swift-XRT–discovered X-ray emission (L_x ≈ 10⁴¹ erg s⁻¹ at 3 days; L_x ∝ t⁻³), and a Shane/Kast spectral detection of narrow Hα and He II emission lines (v ≈ 500 km s⁻¹) originating from pre-existent circumstellar material (CSM). We attribute this phenomenology to radiation from shock interaction with extended, dense material surrounding the progenitor star at r (0.1–1) × 10¹⁷ cm. The photometric and spectroscopic properties during the second light-curve peak are consistent with those of Ca-rich transients (rise-time of t_r = 13.4 ± 0.210 days and a peak B-band magnitude of M_B = −15.1 ± 0.200 mag). We find that SN 2019ehk synthesized (3.1 ± 0.11) × 10⁻² M_⊙ of ⁵⁶Ni and ejected M_(ej) = (0.72 ± 0.040) M⊙ total with a kinetic energy E_k = (1.8 ± 0.10) × 10⁵⁰ erg. Finally, deep HST pre-explosion imaging at the SN site constrains the parameter space of viable stellar progenitors to massive stars in the lowest mass bin (~10 M_⊙) in binaries that lost most of their He envelope or white dwarfs (WDs). The explosion and environment properties of SN 2019ehk further restrict the potential WD progenitor systems to low-mass hybrid HeCO WD+CO WD binaries