Analytical and pharmacological aspects of therapeutic drug monitoring of mTOR inhibitors

Mammalian Target Of Rapamycin (mTOR) inhibitors represent a new class of immunosuppressant drugs extensively used for the prevention and the treatment of graft rejection in organ transplant recipients. Their current use is due to referred low nephrotoxic effects, particularly important in kidney transplanted and/or patients with renal failure. The most representative drugs of such class are Sirolimus (Siro) and Everolimus (Rad). Both drugs show a narrow therapeutic window, therefore, monitoring of whole-blood drug levels is recommended in order to optimize the therapy. Among the available assays, Liquid Chromatography coupled with UltraViolet or Electrospray Tandem Mass Spectrometry methods (LC/UV or LC/ESI-MSMS) are the most accurate and specific ones. A reliable alternative is represented by immunoassays, which offer the opportunity to minimize sample pre-treatment, thus reducing the time between drawing blood sample and measuring the drug concentration, an important aspect in high-throughput analyses. Despite this, a limitation in the use of immunoassays for therapeutic drug monitoring is the lower specifity compared with the chromatographic methods when analysing structurally-related drugs. New insights to optimize mTOR inhibitors regimens seem to be offered by the evaluation of CYP450 3A activity by using the probe drug approach. To such purpose, there are a number of major probe drugs used for in vivo studies including: midazolam, cortisol, lidocaine, nifedipine, dextromethorphan, erythromycin, dapsone and alfentanil. The aim of the present paper is to report the most recent knowledge concerning this issue, supplying a critical and comprehensive review for whom are involved both in the clinical and analytical areas

Pinning potential in highly performant CaKFe4As4 superconductor from DC magnetic relaxation and AC multi-frequency susceptibility studies

We have investigated the pinning potential of high-quality single crystals of superconducting material CaKFe4As4 having high critical current density and very high upper critical field using both magnetization relaxation measurements and frequency-dependent AC susceptibility. Preliminary studies of the superconducting transition and of the isothermal magnetization loops confirmed the high quality of the samples, while temperature dependence of the AC susceptibility in high magnetic fields show absolutely no dependence on the cooling conditions, hence, no magnetic history. From magnetization relaxation measurements were extracted the values of the normalized pinning potential U*, which reveals a clear crossover between elastic creep and plastic creep. The extremely high values of U*, up to 1200 K around the temperature of 20 K lead to a nearly zero value of the probability of thermally-activated flux jumps at temperatures of interest for high-field applications. The values of the creep exponents in the two creep regimes resulted from the analysis of the magnetization relaxation data are in complete agreement with theoretical models. Pinning potentials were also estimated, near the critical temperature, from AC susceptibility measurements, their values being close to those resulted (at the same temperature and DC field) from the magnetization relaxation data

Vortex pinning in Au-irradiated FeSe0.4Te0.6 crystals from the static limit to gigahertz frequencies

Fe(Se,Te) is one of the simplest compounds of iron-based superconductors, but it shows a variety of vortex pinning phenomena both in thin-film and single-crystal forms. These properties are particularly important in light of its potential for applications ranging from the development of coated conductors for high-field magnets to topological quantum computation exploiting the Majorana particles found in the superconducting vortex cores. In this paper, we characterize the pinning properties of FeSe 0.4 Te 0.6 single crystals, both pristine and Au-irradiated, with a set of characterization techniques ranging from the static limit to the GHz frequency range by using dc magnetometry, ac susceptibility measurements of both the fundamental and the third harmonic signals, and by microwave coplanar waveguide resonator measurements of London and Campbell penetration depths. We observed signatures of single vortex pinning that can be modeled by a parabolic pinning potential, dissipation caused by flux creep, and a general enhancement of the critical current density after 320 MeV Au ion irradiation

Chemically exfoliated graphene detects NO2 at the ppb level

Abstract The high sensitivity of graphene to the adsorption/desorption of gas molecule, is at the very beginning of its exploitation. This sensitivity relies on the two-dimensional nature of graphene allowing a total exposure of all its atoms to the adsorbing gas molecules, thus providing the greatest sensor area per unit volume. Indeed several technological limits weigh on the synthesis and manipulation of the material for the device fabrication. Herein a simple approach to fabricate conductometric sensors based on chemically exfoliated natural graphite is presented. The devices were tested upon sub-ppm concentrations of NO 2 in environmental conditions and show the ability to detect this toxic gas down to few ppb at room temperature

Long-term assessment of plasma lipids in transplant recipients treated with tacrolimus in relation to fatty liver.

Immunosuppression has improved graft and recipient survival in transplantation but is associated with possible adverse effects including cardiovascular diseases. The impact of tacrolimus on the lipidic profile has been debated for several years. Twenty-nine kidney transplant recipients on tacrolimus treatment were monitored for six years, and multiple laboratory parameters investigating the lipid asset, as well as glucose profile, were carried out. Tacrolimus has been responsible for significant changes in plasma lipid concentrations only for the first six months, but not for the remaining time of observation. Similarly, in the same periods, glycemic imbalance was highlighted. The liver enzyme activity showed a modest derangement during the tacrolimus treatment, suggesting the presence of lipid accumulation in the liver. Fatty liver reversed in the long term follow-up. Tacrolimus, although it is not a completely safe option in the first months of the immunosuppressive protocols in organ transplanted recipients, still retains a certain role in the long-term post-transplantation immunosuppressive approach with high cardiovascular risk

Magneto-Optical and Multiferroic Properties of Transition-Metal (Fe, Co, or Ni)-Doped ZnO Layers Deposited by ALD

ZnO doped with transition metals (Co, Fe, or Ni) that have non-compensated electron spins attracts particular interest as it can induce various magnetic phenomena and behaviors. The advanced atomic layer deposition (ALD) technique makes it possible to obtain very thin layers of doped ZnO with controllable thicknesses and compositions that are compatible with the main microelectronic technologies, which further boosts the interest. The present study provides an extended analysis of the magneto optical MO Kerr effect and the dielectric properties of (Co, Fe, or Ni)-doped ZnO films prepared by ALD. The structural, magneto optical, and dielectric properties were considered in relation to the technological details of the ALD process and the corresponding dopant effects. All doped samples show a strong MO Kerr behavior with a substantial magnetization response and very high values of the Kerr polarization angle, especially in the case of ZnO/Fe. In addition, the results give evidence that Fe-doped ZnO also demonstrates a ferroelectric behavior. In this context, the observed rich and versatile physical nature and functionality open up new prospects for the application of these nanostructured materials in advanced electronic, spintronic, and optical devices

Retroperitoneal liposarcoma associated with small plaque parapsoriasis

<p>Abstract</p> <p>Background</p> <p>Extremely rare cases of paraneoplastic syndromes or ectopic production of proteins associated with liposarcoma are reported in literature. Production of Granulocyte-Colony Stimulating Factor, alpha-fetoprotein, paraneoplastic pemphigus and leucocytosis, Acrokeratosis paraneoplastica (Bazex's syndrome) are reported.</p> <p>The present report describes a case of retroperitoneal liposarcoma associated with small plaque parapsoriasis. Our search in the English literature of such a kind of association did not reveal any case reported.</p> <p>Case presentation</p> <p>A 74 year male patient was admitted to our hospital because of the presence of an abdominal mass in right iliac fossa. He also complained of a two-year history of psoriasiform eruptions. The CT scan showed a retroperitoneal pelvic mass. Therefore surgical resection of the tumor was performed. After surgery, the skin eruptions disappeared completely in seven days and so a diagnosis of parapsoriasis syndrome was done.</p> <p>Conclusion</p> <p>Parallel disappearing of skin eruptions after surgery, typical clinical picture and not specific histology of the cutaneous lesions suggest the diagnosis of small plaque parapsoriasis. Therefore we propose to add Small Plaque Parapsoriasis to the list of paraneoplastic syndromes associated to liposarcoma.</p

Enhancement of the high-field critical current density of superconducting MgB2 by proton irradiation

A relatively high critical temperature, Tc, approaching 40 K, places the recently-discovered superconductor magnesium diboride (MgB2) intermediate between the families of low- and copper-oxide-based high-temperature superconductors (HTS). Supercurrent flow in MgB2 is unhindered by grain boundaries, unlike the HTS materials. Thus, long polycrystalline MgB2 conductors may be easier to fabricate, and so could fill a potentially important niche of applications in the 20 to 30 K temperature range. However, one disadvantage of MgB2 is that in bulk material the critical current density, Jc, appears to drop more rapidly with increasing magnetic field than it does in the HTS phases. The magnitude and field dependence of Jc are related to the presence of structural defects that can "pin" the quantised magnetic vortices that permeate the material, and prevent them from moving under the action of the Lorentz force. Vortex studies suggest that it is the paucity of suitable defects in MgB2 that causes the rapid decay of Jc with field. Here we show that modest levels of atomic disorder, induced by proton irradiation, enhance the pinning, and so increase Jc significantly at high fields. We anticipate that chemical doping or mechanical processing should be capable of generating similar levels of disorder, and so achieve technologically-attractive performance in MgB2 by economically-viable routes.Comment: 5 pages, 4 figures, to be published in Nature (in press