Efflux transport of nicotine, cotinine and trans-3 '-hydroxycotinine glucuronides by human hepatic transporters

Nicotine is the addiction causing alkaloid in tobacco, and it is used in smoking cessation therapies. Although the metabolic pathways of nicotine are well known and mainly occur in the liver, the transport of nicotine and its metabolites is poorly characterized. The highly hydrophilic nature and urinary excretion of nicotine glucuronide metabolites indicate that hepatic basolateral efflux transporters mediate their excretion. We aimed here to find the transporters responsible for the hepatic excretion of nicotine, cotinine and trans-3 '-hydroxycotinine (OH-cotinine) glucuronides. To this end, we tested their transport by multidrug resistance-associated proteins 1 (MRP1, ABCC1) and MRP3-6 (ABCC3-6), which are located on the basolateral membranes of hepatocytes, as well as MRP2 (ABCC2), breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance protein 1 (MDR1, P-gp, ABCB1) that are expressed in the apical membranes of these cells. ATP-dependent transport of these glucuronides was evaluated in inside-out membrane vesicles expressing the transporter of interest. In addition, potential interactions of both the glucuronides and parent compounds with selected transporters were tested by inhibition assays. Considerable ATP-dependent transport was observed only for OH-cotinine glucuronide by MRP3. The kinetics of this transport activity was characterized, resulting in an estimated K-m value of 895 mu mol/L. No significant transport was found for nicotine or cotinine glucuronides by any of the tested transporters at either 5 or 50 mu mol/L substrate concentration. Furthermore, neither nicotine, cotinine nor OH-cotinine inhibited MRP2-4, BCRP or MDR1. In this study, we directly examined, for the first time, efflux transport of the three hydrophilic nicotine glucuronide metabolites by the major human hepatic efflux transporters. Despite multiple transporters studied here, our results indicate that an unknown transporter may be responsible for the hepatic excretion of nicotine and cotinine glucuronides.Peer reviewe

Spectroscopic signatures of magnetospheric accretion in Herbig Ae/Be stars. I. The case of HD101412

Models of magnetically-driven accretion and outflows reproduce many observational properties of T Tauri stars. This concept is not well established for the more massive Herbig Ae/Be stars. We intend to examine the magnetospheric accretion in Herbig Ae/Be stars and search for rotational modulation using spectroscopic signatures, in this first paper concentrating on the well-studied Herbig Ae star HD101412. We used near-infrared spectroscopic observations of the magnetic Herbig Ae star HD101412 to test the magnetospheric character of its accretion disk/star interaction. We reduced and analyzed 30 spectra of HD101412, acquired with the CRIRES and X-shooter spectrographs installed at the VLT (ESO, Chile). The spectroscopic analysis was based on the He I lambda 10,830 and Pa gamma lines, formed in the accretion region. We found that the temporal behavior of these diagnostic lines in the near-infrared spectra of HD101412 can be explained by rotational modulation of line profiles generated by accreting gas with a period P = 20.53+-1.68 d. The discovery of this period, about half of the magnetic rotation period P_m = 42.076 d previously determined from measurements of the mean longitudinal magnetic field, indicates that the accreted matter falls onto the star in regions close to the magnetic poles intersecting the line-of-sight two times during the rotation cycle. We intend to apply this method to a larger sample of Herbig Ae/Be stars.Comment: 8 pages, 1 table, 7 figures, accepted for publication in A&

Hurricane risk analysis: A review on the physically-based approach

This paper reviews recent studies that take a physically-based approach to better assess and manage hurricane risk. Such a methodology includes three components: modeling the storm climatology (which defines TC risk in terms of the upper tail of the storm statistics); modeling landfalling hazards; and characterizing damage and losses

Polymers for nuclear materials processing

This is the final report of a one-year, Laboratory-Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). The use of open-celled microcellular foams as solid sorbents for metal ions and other solutes could provide a revolutionary development in separation science. Macroreticular and gel-bead materials are the current state-of-the-art for solid sorbents to separate metal ions and other solutes from solution. The new polymer materials examined in this effort offer a number of advantages over the older materials that can have a large impact on industrial separations. The advantages include larger usable surface area in contact with the solution, faster sorption kinetics, ability to tailor the uniform cell size to a specific application, and elimination of channeling and packing instability

The experience of long-term opiate maintenance treatment and reported barriers to recovery: A qualitative systematic review

Background/Aim: To inform understanding of the experience of long-term opiate maintenance and identify barriers to recovery. Methods: A qualitative systematic review. Results: 14 studies in 17 papers, mainly from the USA (65%), met inclusion criteria, involving 1,088 participants. Studies focused on methadone prescribing. Participants reported stability; however, many disliked methadone. Barriers to full recovery were primarily ‘inward focused'. Conclusion: This is the first review of qualitative literature on long-term maintenance, finding that universal service improvements could be made to address reported barriers to recovery, including involving ex-users as positive role models, and increasing access to psychological support. Treatment policies combining harm minimisation and abstinence-orientated approaches may best support individualised recovery

Deformations at Earth's dayside magnetopause during quasi-radial IMF conditions: Global kinetic simulations and soft X-ray imaging

The Solar wind Magnetosphere Ionosphere Link Explorer (SMILE) is an ESA-CAS joint mission. Primary goals are investigating the dynamic response of the Earth's magnetosphere to the solar wind (SW) impact via simultaneous in situ magnetosheath (MS) plasma and magnetic field measurements, X-Ray images of the magnetosheath and magnetic cusps, and UV images of global auroral distributions. Magnetopause (MP) deformations associated with MS high speed jets (HSJs) under a quasi-parallel interplanetary magnetic field condition are studied using a three-dimensional (3-D) global hybrid simulation. Soft X-ray intensity calculated based on both physical quantities of solar wind proton and oxygen ions is compared. We obtain key findings concerning deformations at the MP: (1) MP deformations are highly coherent with the MS HSJs generated at the quasiparallel region of the bow shock, (2) X-ray intensities estimated using solar wind H+ and self-consistent O7+ ions are consistent with each other, (3) Visual spacecraft are employed to check the discrimination ability for capturing MP deformations on Lunar and polar orbits, respectively. The SMILE spacecraft on the polar orbit could be expected to provide opportunities for capturing the global geometry of the magnetopause in the equatorial plane. A striking point is that SMILE has the potential to capture small-scale MP deformations and MS transients, such as HSJs, at medium altitudes on its orbit

The holographic quantum effective potential at finite temperature and density

We develop a formalism that allows the computation of the quantum effective potential of a scalar order parameter in a class of holographic theories at finite temperature and charge density. The effective potential is a valuable tool for studying the ground state of the theory, symmetry breaking patterns and phase transitions. We derive general formulae for the effective potential and apply them to determine the phase transition temperature and density in the scaling region.Comment: 27 page

Comparison of insulin glargine and liraglutide added to oral agents in patients with poorly controlled type 2 diabetes

Peer reviewe

Gastrocnemius vs. soleus strain: how to differentiate and deal with calf muscle injuries

Calf strains are common injuries seen in primary care and sports medicine clinics. Differentiating strains of the gastrocnemius or soleus is important for treatment and prognosis. Simple clinical testing can assist in diagnosis and is aided by knowledge of the anatomy and common clinical presentation