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The mechanochemical reaction between copper and dimethyl disulfide is studied under well-controlled conditions in ultrahigh vacuum (UHV). Reaction is initiated by fast S–S bond scission to form adsorbed methyl thiolate species, and the reaction kinetics are reproduced by two subsequent elementary mechanochemical reaction steps, namely a mechanochemical decomposition of methyl thiolate to deposit sulfur on the surface and evolve small, gas-phase hydrocarbons, and sliding-induced oxidation of the copper by sulfur that regenerates vacant reaction sites. The steady-state reaction kinetics are monitored in situ from the variation in the friction force as the reaction proceeds and modeled using the elementary-step reaction rate constants found for monolayer adsorbates. The analysis yields excellent agreement between the experiment and the kinetic model, as well as correctly predicting the total amount of subsurface sulfur in the film measured using Auger spectroscopy and the sulfur depth distribution measured by angle-resolved X-ray photoelectron spectroscopy.

•A decline in the frequency of HIV resistance mutations to old drug classes was observed.•The levels of HIV RNA have been decreasing over time.•An increase in N155H mutation was documented.

A 23-year-old white man was admitted to the hospital for evaluation of recurrent hemoptysis. He denied any other associated symptoms, including dyspnea, chest pain, productive cough, wheezing, fever, or weight loss. He had no significant past medical history and was not taking any medication. He had no significant family history for cardiopulmonary diseases.

A chronoamperometric method has been applied for the growth of a surface coating on AZ31B magnesium alloy, using the imidazolium alkylphosphonate room-temperature ionic liquid 1-ethyl-3-methylimidazolium ethylphosphonate ([EMIM][EtPO3H]) as electrolyte. A surface coating layer is obtained after 4 h under a constant voltage bias of −0.8 V with respect to the standard electrode. The coating nucleation and growth process correlates well with a 3D progressive mechanism. X-ray photoelectron spectrometry (XPS) analysis of [EMIM][EtPO3H] shows new P 2p and O 1s peaks after its use as electrolyte, as a consequence of reaction between the phosphonate anion and the magnesium substrate. Angle-resolved XPS (ARXPS) analysis of [EMIM][EtPO3H] did not show any change in the composition of the surface before and after chronoamperometry, since the sampling depth (1.5 nm at the highest emission angle) is larger than the cation and anion sizes (ca. 7 and 5 Å, respectively). Characterization of the coating was made by scanning electron microscopy (SEM), focussed ion beam SEM, energy dispersive X-ray spectroscopy, XPS, and ARXPS. FIB-SEM shows that the coating presents a mean thickness of 374 (±36) nm and contains magnesium and aluminum phosphates. Linear reciprocating tribological tests under variable load show that the presence of the coating can reduce friction coefficients of the coated AZ31B against steel up to 32% and wear rates up to 90%, with respect to the uncoated alloy.

The human immunodeficiency virus type-1 (HIV-1) integrase enzyme has recently emerged as a primary alternative target to block viral replication, and integrase strand transfer inhibitors (INSTIs) are now considered an alternative ‘third agent’ class of antiretroviral (ARV) drugs. Dolutegravir is the first next-generation INSTI showing some novel and intriguing characteristics: it has a favorable pharmacokinetic profile with a prolonged intracellular halflife, rendering feasible a once daily dosing without the need for pharmacokinetic boosting. Secondly, it is largely metabolized via uridine diphosphate glucuronosyltransferase-1A1 with a minor component of cytochrome P450 isoforms, thus allowing a low grade of drug–drug interactions, so that its metabolic profile consents co-administration with the majority of the other ARV drugs without dose adjustments. Lastly, but no less important, virological studies have clearly demonstrated that dolutegravir has a significant activity against HIV-1 isolates showing raltegravir and/or elvitegravir associated resistance mutations. The attributes of once daily administration and the potential to treat INSTI-resistant viruses make dolutegravir an interesting and promising new agent in the treatment of both naïve and experienced HIV-1 subjects. In this review, the main concerns on dolutegravir efficacy are focused through the analysis of the currently available data from clinical studies in naïve and experienced patients, evaluating its possible place within the anti-HIV-1 drug armamentarium. The development of newer once daily, single tablet coformulations improved drug adherence and maximized the success of ARV therapy. Pharmacokinetic studies and dose-ranging trials suggested that dolutegravir is a good candidate for a single tablet regimen in one or more new coformulated pills that will be available in the near future.

Background The HIV integrase inhibitor raltegravir (RAL) can exacerbate autoimmune diseases in genetically predisposed mice. To evaluate whether this may occur in clinical practice, we clinically monitored HIV-positive patients treated with RAL and measured a panel of autoantibodies (auto-Abs) during the first year of RAL treatment.Methods This was a longitudinal study in 109 antiretroviral-experienced patients who started a RAL-based regimen and were followed up for more than 2 years. A total of 45 patients were tested at baseline (before starting RAL) and after 12 months for the presence of the following auto-Abs: anti-nuclear antibodies, anti-double-stranded DNA, anti-smooth-muscle antibodies, anti-thyreoglobulin and anti-thyroid peroxidase antibodies, anti-cardiolipin immunoglobulin G and immunoglobulin M and anti-nuclear extractable antigens, including anti-SM ribonucleoprotein antigen, anti-Ro antigen and anti-La antigen.Results A low rate of clinically relevant autoimmune diseases was observed at study entry (3/109; 2.8%; 95% CI 0.004, 0.059). No exacerbations were observed during follow-up. During the second year of RAL-based therapy a previously healthy patient developed psoriasis. At baseline, 17/45 (37.8%) patients tested for the presence of auto-Abs were positive. Most patients (n=13) were positive for anti-cardiolipin. After 12 months of RAL exposure, 9/45 patients were positive (20%; P=0.063). A positive correlation was found between HIV-1 RNA and anti-cardiolipin antibody concentration (P=0.010).Conclusions According to these results, RAL does not promote antibody-mediated immune disorders, at least not in the mid-term. A prolonged follow-up and an extension of the panel of auto-Abs are recommended to support these results.

Motivated by our previous studies on metallic substrates, in the present work we addressed the functionalization and the subsequent metallization of a hydrogen-terminated n-Si(111) electrode. DFT provides atomistic insights on the grafting mechanism of 4-pyridinecarboxaldehyde (C6H5NO) what encouraged electrochemical investigations, i. e.cyclic voltammetry and in-situSTM, combined with XPS measurements which together provide evidence for a successful transfer of the so far obtained knowledge from metal single crystal to semiconductor surfaces.

The presence of hydrotalcite-like sulphates such as glaucocerinite and zincowoodwardite [(Zn, Cu)1-xAlx(SO4)x/2(OH)2 · mH2O] has been documented in a number of mining areas. They usually occur as fine-grained precipitates from mining waters or as porous crusts. While their role on removing cations such as Zn, Cu and Al from waters is immediately evident, the role they have in incorporating anions, other than (SO4)2-, is often disregarded. However, field evidences from a mine area in Sardinia (Italy) showed that these phases have a great capability to remove arsenic from waters. An extremely variable composition and low degree of structural order make natural HTs difficult to be characterized. For this reason a combination of several analytical techniques (ICP-OES, XRD, CHNS, SEM-EDX, TEM-EDX, IR, XPS) was adopted to obtain a good characterization of investigated samples from Baccu Locci. Along with field investigations, laboratory experiments on synthetic phases showed that glaucocerinite and zincowoodwardite remove As from waters, mostly through exchange processes, due to the strong capability of (AsO4)3- in replacing (SO4)2- in the interlayer of HTs structure, where anionic groups are hosted. The advantage of HT-like sulphates, in comparison with Fe-oxides-hydroxides (generally considered the most efficient arsenic removers, naturally occurring in mining areas), is to act as removers in waters at high pH values, when a reduced efficiency of Fe-oxides-hydroxides in arsenic sorption and a greater arsenic mobility account for an increased arsenic hazard.

In clinical practice, patients with a range of signs and symptoms suggestive of connective tissue disease, but who do not fulfil the classification criteria for a defined disease are often found. This condition is defined as “Undifferentiated Connective Tissue Disease” (UCTD). Most of the authors consider UCTD as a distinct clinical entity, generally stable during follow-up. Despite this, no mutual agreement regarding criteria for its diagnosis has been reached. The clinical, serological, therapeutical and evolutional patterns of 41 patients initially diagnosed as having early UCTD during a 3-year follow-up are described in this study. At the end of the observational period, 21% of the enrolled patients, followed throughout the follow-up, demonstrated clinical evolution to a defined connective tissue disease (CTD), whereas 52% of the observed subjects maintained an undifferentiated profile with variable clinical findings and presenting a generally stable disease over time. The remaining patients showed clinical improvement or complete regression of the symptoms associated with normalization of the inflammatory indexes. The role of therapy in these different clinical courses is discussed.

The addition of Ru3CO12, dimethyl carbonate, or both to the reaction mixture improves the selectivity of the palladiumphenanthrolinecatalyzed reaction of nitroarenes, arylalkynes, and CO to give 3arylindoles. When 4fluorophenylacetylene and nitrobenzene are used as substrates, the indole skeleton of Fluvastatin and other pharmaceutically active compounds is obtained in one step.© WileyVCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009

Herein we report the one‐pot synthesis of several N‐heterocyclic compounds by rearrangement reactions of N‐aryl‐2‐vinylaziridines. The optimization of the synthetic methodology employed allowed us to obtain differently substituted 2,5‐dihydro‐1H‐benzo[b]azepines in good yields and purities. The relationship between the nature of the starting N‐aryl‐2‐vinylaziridine and the obtained N‐heterocycle was also investigated. Finally, to rationalize all the experimental results reported in this paper a theoretical study was performed that casts light on the reaction mechanism.

Epidermolysis bullosa (EB) is a group of skin diseases with different clinical manifestations and varied inheritance patterns. Blisters may appear spontaneously or following minimal trauma to the skin or mucosa.

CoIItpp catalyzes the reaction of aromatic azides ArN3 with nonactivated olefins to yield allylic amines or aziridines in moderatetogood yields. The chemoselectivity of the catalytic reaction is particularly high. Depending on the substrate employed, allylic amines or aziridines can be obtained. The reaction mechanism was investigated, and the reaction proceeds through reversible coordination of the aryl azide to the CoII–porphyrin complex. The often postulated “nitrene” complex is not an intermediate in this reaction. The kinetics for the allylic amination is first order in azide, Cotpp, and olefin. For the aziridination, the kinetics is again first order in azide and catalyst, but we observed a firstorder dependence of the rate on αmethylstyrene only up to an olefin concentration of 6.9 M. An inhibiting role of the competitively formed 14nitrophenyl5methyl5phenyl1,2,3triazoline was identified. The triazoline was shown to reversibly coordinate to Cotpp, which blocks the free coordination site necessary for the catalytic reaction to proceed, and is it responsible for the catalyst deactivation in the aziridination reaction of αmethylstyrene by 4nitrophenyl azide. © WileyVCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008

Aryl azides have been used as atom-efficient nitrene transfer reagents in the (porphyrin)ruthenium-catalyzed amination of olefins. Several azides, olefins and [Ru(porphyrin)CO] complexes were tested to investigate the scope and limits of the reaction. Quantitative yields and short reaction times were achieved by using terminal olefins and aryl azides bearing electron-withdrawing groups on the aryl moiety. The reactions were influenced by steric factors. Internally disubstituted olefins exhibited a lower reactivity and tri- and tetrasubstituted olefins did not react at all. A very high turnover number (TON) for the [Ru(TPP)CO] (TPP = tetraphenylporphyrin dianion) catalyzed amination of α-methylstyrene by p-nitrophenyl azide was obtained.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

[Ru(CO)(porphyrin)] complexes have been found to catalyze the direct aziridination of conjugated dienes by aryl azides with high chemoselectivity, to provide N-aryl-2-vinylaziridines. To determine the scope of the reaction, several hydrocarbons and azides were tested. The reactions between 2,3-dimethylbuta-1,3-diene and aryl azides bearing electron-withdrawing groups in the para or meta positions in their aryl moieties occur very efficiently in short times, while the selectivities of the aziridinations are governed by the steric hindrances of the double bonds, so lower yields are registered with sterically encumbered 1,4-disubstituted dienes, though it is worth noting that the aziridination of trans,trans-1,4-diphenylbuta-1,3-diene was stereospecific and that only one isomer was obtained. The aza-[3,3]-Claisen rearrangement of 2-isopropenyl-2-methyl-N-(4-nitrophenyl)aziridine to produce the corresponding 2,5-1H-benzo[b]azepine is also reported.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

The application of reductive carbonylation of nitroarenes to the synthesis of fine chemicals is described. The review focuses on the results reported from 1996 onwards and is mainly divided in two parts, respectively describing the intra-molecular cyclization reactions of nitroarenes bearing in the ortho position a suitable functional group and the intermolecular reactions of nitroarenes with external olefins and alkynes. Benzo-fused heterocycles such as indoles and quinolinones are obtained by the first group of reactions, whereas allylic amines, oxazines, pyrroles and indoles are the products of inter-molecular reactions. Mechanistic studies are also discussed in a separate section. x

The reaction of Ru(TPP)CO (TPP = dianion of tetraphenylporphyrin) with 1-(p-nitrophenyl)-5-methyl-5-phenyl-1,2,3-triazoline yielded a Δ²-1,2,3-triazoline ruthenium(II) porphyrin complex, which is responsible for the catalyst deactivation in the aziridination reaction of α-methylstyrene by p-nitrophenyl azide.

We report the development of a sensitive and specific color test for the detection of the presence of resin-bound aldehyde groups using 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole (Purpald). Aldehyde resin turns dark-brown to purple after a 5 min reaction followed by a 10 min air oxidation period. Resins that possess other functional groups (i.e., ketone, ester, amide, alcohol, and carboxylic acid) do not change color under the same conditions. The detection limit is 20 μmol/g for polystyrene-based aldehyde resins.

A series of libraries containing the 2,4-diaminoquinazoline ring system were prepared, starting from polymer-bound amines. The key steps included reaction of the support-bound amine with 6,7-dimethoxy-2,4-dichloroquinazoline, followed by displacement of the second chlorine with an amine and subsequent TFA-mediated cleavage of the product from the support. When a symmetrical or unsymmetrical diamine was used in the displacement step, the free amine could be acylated with an activated acid to generate another set of compounds. The optimization of conditions for the reductive amination and displacement steps will be discussed as well as the final choice of resin for library production. In addition, quality control methods for library analysis is also described.

Convenient and reliable large-scale procedures for the protection of various amino acids with N-(9-fluorenylmethoxycarbonyl)oxysuccinimide (FMOC-OSu) are described. Commercially available 4-aminomethylbenzoic acid and trans-4-(aminomethyl)cyclohexanecarboxylic acid were converted into their corresponding FMOC-derivatives in excellent yields without the need for an extractive workup. In addition, FMOC-cis-β-amino acids were also prepared, employing a [2 + 2]-cycloaddition strategy between a cyclic olefin and N-chlorosulfonyl isocyanate (CSI). The resulting N-chlorosulfonyl β-lactams were reduced to the parent β-lactams with sodium sulfite and then converted to the cis-β-amino acid hydrochlorides by exposure to aqueous hydrochloric acid. The resulting cis-β-amino acids were converted to their FMOC-derivatives under conditions similar to those developed for the commercially available amino acids. Differences in the conditions employed between these β-amino acids and the commercial derivatives were observed, primarily in the nature of the base required for the reaction. A possible rationale for the differences in behavior is described. These FMOC-amino acid derivatives are valuable intermediates for the solid-phase synthesis of combinatorial libraries.

A practical method for solid phase organic synthesis has been developed using the known, but heretofore underutilized, 4-hydroxythiophenol linker of Marshall and Liener. The utility of this linker is demonstrated by the synthesis of 1,2,3,4-tetrahydro-β-carboline-3-carboxamides and -2,3-bis-lactams. Acylation of the resin with L-Boc-tryptophan followed by deprotection and Pictet-Spengler cyclization with a variety of aldehydes provided tetrahydro-β-carbolines with excellent conversion. Cleavage from the resin with primary amines provided the amides and an additional diversity element. Alternatively, acylation at the carboline 2-position with Boc- protected α- or β-amino acid derivatives followed by deprotection and neutralization resulted in intramolecular cyclization and cleavage to afford 6- and 7-membered bis-lactams.

Gentamicin nephrotoxicity is associated with impaired glomerular function. To examine whether the effects of gentamicin on glomerular function are mediated through alterations in the renal-angiotensin system, basal and stimulated glomerular renin release was assessed in isolated glomeruli from control and gentamicin-treated rats. Male Sprague-Dawley rats (220 ± 20 g) were studied immediately after treatment with gentamicin sulfate (4 mg/kg BW/day, n = 6) for 1 or 2 consecutive weeks and after 1 week of recovery from 2 weeks of treatment. Control rats received an equivalent volume of saline (n = 9). After the respective treatment, renal renin content was measured. In addition, glomeruli from control and gentamicin-treated rats were isolated and glomerular renin release was measured under basal conditions and after stimulation with the calmodulin inhibitor trifluoperazine (1 × 10-4 M). Renin concentration was determined in aliquots of the supernatant by measuring the generation of angiotensin I using radioimmunoassay techniques at 15-min intervals. Renal renin content was significantly increased after 2 weeks of gentamicin treatment (+47%) and remained elevated (+ 62%) 1 week after discontinuing a 2-week gentamicin treatment. Both basal and stimulated glomerular renin release were lower in glomeruli isolated from gentamicin-treated rats. The effect of gentamicin added in vitro to glomeruli isolated from untreated rats was also evaluated. Exposure of normal glomeruli to in vitro gentamicin (1 mM) resulted in a Significant inhibition of both basal (-47%, p < .05) and stimulated (-84%, p < .05) glomerular renin release. To determine whether the inhibitory action of gentamicin on glomerular renin release was dependent on extracellular calcium concentration, the effects of gentamicin on glomerular renin release were also assessed in the absence of extracellular calcium. Our data revealed that in the absence of extracellular calcium, the inhibitory effect of gentamicin on both basal and stimulated glomerular renin release was abolished. Taken together, these findings strongly suggest an inhibitory effect of gentamicin on glomerular renin release. Furthermore, the inhibition of glomerular renin release induced by gentamicin appears to be dependent on extracellular calcium.

Drury: Prevention Genetics: Employment.

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