Long-term side-effects and cost of HIV treatment motivate the development of simplified maintenance. Monotherapy with ritonavir-boosted lopinavir (LPV/r-MT) is the most widely studied strategy. ...However, efficacy of LPV/r-MT in compartments remains to be shown.
Randomized controlled open-label trial comparing LPV/r-MT with continued treatment for 48 weeks in treated patients with fully suppressed viral load. The primary endpoint was treatment failure in the central nervous system cerebrospinal fluid (CSF) and/or genital tract. Treatment failure in blood was defined as two consecutive HIV RNA levels more than 400 copies/ml.
The trial was prematurely stopped when six patients on monotherapy (none in continued treatment-arm) demonstrated a viral failure in blood. At study termination, 60 patients were included, 29 randomized to monotherapy and 13 additional patients switched from continued treatment to monotherapy after 48 weeks. All failures occurred in patients with a nadir CD4 cell count below 200/microl and within the first 24 weeks of monotherapy. Among failing patients, all five patients with a lumbar puncture had an elevated HIV RNA load in CSF and four of six had neurological symptoms. Viral load was fully resuppressed in all failing patients after resumption of the original combination therapy. No drug resistant virus was found. The only predictor of failure was low nadir CD4 cell count (P < 0.02).
Maintenance of HIV therapy with LPV/r alone should not be recommended as a standard strategy; particularly not in patients with a CD4 cell count nadir less than 200/microl. Further studies are warranted to elucidate the role of the central nervous system compartment in monotherapy-failure.
OBJECTIVES:To determine HIV-1 RNA in cerebrospinal fluid (CSF) of successfully treated patients and to evaluate if combination antiretroviral treatments with higher central nervous system ...penetration-effectiveness (CPE) achieve better CSF viral suppression.
METHODS:Viral loads (VLs) and drug concentrations of lopinavir, atazanavir, and efavirenz were measured in plasma and CSF. The CPE was calculated using 2 different methods.
RESULTS:The authors analyzed 87 CSF samples of 60 patients. In 4 CSF samples, HIV-1 RNA was detectable with 43–82 copies per milliliter. Median CPE in patients with detectable CSF VL was significantly lower compared with individuals with undetectable VLCPE of 1.0 (range, 1.0–1.5) versus 2.3 (range, 1.0–3.5) using the method of 2008 (P = 0.011) and CPE of 6 (range, 6–8) versus 8 (range, 5–12) using the method of 2010 (P = 0.022). The extrapolated CSF trough levels for atazanavir (n = 12) were clearly above the 50% inhibitory concentration (IC50) in only 25% of samples; both patients on atazanavir/ritonavir with detectable CSF HIV-1 RNA had trough levels in the range of the presumed IC50. The extrapolated CSF trough level for lopinavir (n = 42) and efavirenz (n = 18) were above the IC50 in 98% and 78%, respectively, of samples, including the patients with detectable CSF HIV-1 RNA.
CONCLUSIONS:This study suggests that treatment regimens with high intracerebral efficacy reflected by a high CPE score are essential to achieve CSF HIV-1 RNA suppression. The CPE score including all drug components was a better predictor for treatment failure in the CSF than the sole concentrations of protease inhibitor or nonnucleoside reverse transcriptase inhibitor in plasma or CSF.
Functional hybrid materials on the basis of inorganic hosts and ionic liquids (ILs) as guests hold promise for a virtually unlimited number of applications. In particular, the interaction and the ...combination of properties of a defined inorganic matrix and a specific IL could lead to synergistic effects in property selection and tuning. Such hybrid materials, generally termed ionogels, are thus an emerging topic in hybrid materials research. The current article addresses some of the recent developments and focuses on the question why silica is currently the dominating matrix used for (inorganic) ionogel fabrication. In comparison to silica, matrix materials such as layered simple hydroxides, layered double hydroxides, clay-type substances, magnetic or catalytically active solids, and many other compounds could be much more interesting because they themselves may carry useful functionalities, which could also be exploited for multifunctional hybrid materials synthesis. The current article combines experimental results with some arguments as to how new, advanced functional hybrid materials can be generated and which obstacles will need to be overcome to successfully achieve the synthesis of a desired target material.
Accurate translation of genetic information into protein sequence depends on complete messenger RNA molecules. Truncated mRNAs cause synthesis of defective proteins, and arrest ribosomes at the end ...of their incomplete message. In bacteria, a hybrid RNA molecule that combines the functions of both transfer and messenger RNAs (called tmRNA) rescues stalled ribosomes, and targets aberrant, partially synthesized, proteins for proteolytic degradation. Here we report the 3.2-Å-resolution structure of the tRNA-like domain of tmRNA (tmRNAΔ) in complex with small protein B (SmpB), a protein essential for biological functions of tmRNA. We find that the flexible RNA molecule adopts an open L-shaped conformation and SmpB binds to its elbow region, stabilizing the single-stranded D-loop in an extended conformation. The most striking feature of the structure of tmRNAΔ is a 90° rotation of the TΨC-arm around the helical axis. Owing to this unusual conformation, the SmpB-tmRNAΔ complex positioned into the A-site of the ribosome orients SmpB towards the small ribosomal subunit, and directs tmRNA towards the elongation-factor binding region of the ribosome. On the basis of this structure, we propose a model for the binding of tmRNA on the ribosome.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Transition metal (TM) hydrides are of great interest in chemistry because of their reactivity and their potential as catalysts for hydrogenation reactions. 2H solid-state NMR can be used in order to ...get information about the local environment of hydrogen atoms, and more particularly the coordination mode of hydrides in such complexes. In this work we will show that it is possible to establish at the level of density functional theory (DFT) a viable methodological strategy that allows the determination of 2H NMR parameters, namely the quadrupolar coupling constant (C(Q)) respectively the quadrupolar splitting (deltanuQ) and the asymmetry parameter (etaQ). The reliability of the method (B3PW91-DFT) and basis set effects have been first evaluated for simple organic compounds (benzene and fluorene). A good correlation between experimental and theoretical values is systematically obtained if the large basis set cc-pVTZ is used for the computations. 2H NMR properties of five mononuclear ruthenium complexes (namely Cp*RuD3(PPh3), Tp*RuD(THT)2, Tp*RuD(D2)(THT) and Tp*RuD(D2)2 and RuD2(D2)2(PCy3)2) which exhibit different ligands and hydrides involved in different coordination modes (terminal-H or eta2-H2), have been calculated and compared to previous experimental data. The results obtained are in excellent agreement with experiments. Although 2H NMR spectra are not always easy to analyze, assistance by quantum chemistry calculations allows unambiguous assignment of the signals of such spectra. As far as experiments can be achieved at very low temperatures in order to avoid dynamic effects, this hybrid theoretical/experimental tool may give useful insights in the context of the characterization of ruthenium surfaces or nanoparticles with solid-state NMR.
Identification and imaging of crystallographic phases inside an object can be achieved by time-of-flight neutron diffraction, based on a correction formula that is usually used to account for a ...sample offset on a powder diffractometer. The procedure allows the distribution of crystallographic phases along the incident beam path through the thickness of the material to be reconstructed. Phase reconstruction is demonstrated on a benchmark object.
Geometrical frustration arises when geometrical constraints promote a locally degenerate ground state. A periodic system with this local geometry may “freeze” on cooling forming “ices” or remain ...liquid down to the lowest temperatures due to quantum effects. A third possibility is that of a structural phase transition that lowers the local symmetry and lifts the degeneracy. Two classic examples of geometrical frustration are the so-called pyrochlore lattice, which is also found in AB
2X
4 spinels, and the “
J
1–
J
2” model on a square lattice, which involves competing nearest- and next-near-neighbor magnetic interactions. We present recent results obtained by time-of-flight (TOF) neutron powder diffraction on orbital ordering in transition-metal spinels, leading to the concept of orbitally-driven Peierls state, and more recent data on MoOVO
4, a realization of the
J
1–
J
2 model. A surge of interest in the so-called multiferroic materials has led to revisit the role of geometrical frustration in coupling different degrees of freedom. In this context, we present recent results on REMn
2O
5 obtained by neutron single-crystal and powder diffraction.
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