Reversible Single-Electron-Transfer to Oxygen in a Stable N-Heterocyclic Carbene Palladium(I) Metalloradical.

The chemical and electrochemical one-electron oxidation of [Pd(IPr)2] (1) leads to the formation of mononuclear palladium(I) complex [Pd(IPr)2][PF6] (2). This bench-stable metalloradical has been fully characterized and its structure confirmed by X-ray diffraction analysis. EPR and DFT studies confirm the localization of the unpaired electron onto the metal center. Low temperature NMR and EPR measurements reveal the ability of complex 2 to reversibly coordinate and reduce the dioxygen molecule, leading to the formation of a three-coordinate complex, [PdII(IPr)2(η1-O2)]+ (4), in which the unpaired electron has been transferred to the superoxido ligand.

Synthesis of Water-Soluble Palladium Nanoparticles Stabilized by Sulfonated N-Heterocyclic Carbenes.

A strategy involving the decomposition of palladium(II) organometallic complexes with sulfonated N-heterocyclic carbene ligands leads to the formation of stable and water-soluble Pd nanoparticles. Three different methodologies (thermal decomposition, reduction under 13 CO atmosphere, and reduction with H2 ) gave particles with different shapes and sizes, ranging from 1.5 to 7 nm. The structures of the organometallic intermediates and organic decomposition products were elucidated by NMR spectroscopy. To check the accessibility of the surface, the nanoparticles were tested as catalysts for the chemoselective hydrogenation of styrene in water. An effect of the particle size on the catalyst activity was observed. The aqueous phase was recycled up to ten times without any precipitation of metallic palladium.

Knight Shift in 13 C†NMR Resonances Confirms the Coordination of N-Heterocyclic Carbene Ligands to Water-Soluble Palladium Nanoparticles.

The coordination of N-heterocyclic carbene (NHC) ligands to the surface of 3.7 nm palladium nanoparticles (PdNPs) can be unambiguously established by observation of Knight shift (KS) in the 13 C resonance of the carbenic carbon. In order to validate this coordination, PdNPs with sizes ranging from 1.3 to 4.8 nm were prepared by thermal decomposition or reduction with CO of a dimethyl NHC PdII complex. NMR studies after 13 CO adsorption established that the KS shifts the 13 C resonances of the chemisorbed molecules several hundreds of ppm to high frequencies only when the particle exceeds a critical size of around 2 nm. Finally, the resonance of a carbenic carbon is reported to be Knight-shifted to 600 ppm for 13 C-labelled NHCs bound to PdNPs of 3.7 nm. The observation of these very broad KS resonances was facilitated by using Car-Purcell-Meiboom-Gill (CPMG) echo train acquisition NMR experiments.

Quality-of-care standards for early arthritis clinics.

The diagnosis and treatment of early arthritis is associated with improved patient outcomes. One way to achieve this is by organising early arthritis clinics (EACs). The objective of this project was to develop standards of quality for EACs. The standards were developed using the two-round Delphi method. The questionnaire, developed using the best-available scientific evidence, includes potentially relevant items describing the dimensions of quality of care in the EAC. The questionnaire was completed by 26 experts (physicians responsible for the EACs in Spain and chiefs of the rheumatology service in Spanish hospitals). Two hundred and forty-four items (standards) describing the quality of the EAC were developed, grouped by the following dimensions: (1) patient referral to the EAC; (2) standards of structure for an EAC; (3) standards of process; (4) relation between primary care physicians and the EAC; (5) diagnosis and assessment of early arthritis; (6) patient treatment and follow-up in the EAC; (7) research and training in an EAC; and (8) quality of care perceived by the patient. An operational definition of early arthritis was also developed based on eight criteria. The standards developed can be used to measure/establish the requirements, resources, and processes that EACs have or should have to carry out their treatment, research, and educational activities. These standards may be useful to health professionals, patient associations, and health authorities.

Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice.

OBJECTIVE: To evaluate the safety and efficacy of tocilizumab in clinical practice in patients with rheumatoid arthritis (RA) with inadequate responses (IR) to disease-modifying antirheumatic drugs (DMARDs) or both DMARDs and tumour necrosis factor α inhibitors (TNFis). METHODS: Patients-categorised as TNFi-naive, TNFi-previous (washout) or TNFi-recent (no washout) -received open-label tocilizumab (8 mg/kg) every 4 weeks ± DMARDs for 24 weeks. Adverse events (AEs) and treatment discontinuations were monitored. Efficacy end points included American College of Rheumatology (ACR) responses, 28-joint disease activity score (DAS28) and European League Against Rheumatism responses. RESULTS: Overall, 1681 (976 TNF-naive, 298 TNFi-previous and 407 TNFi-recent) patients were treated; 5.1% discontinued treatment because of AEs. The AE rate was numerically higher in TNFi-recent (652.6/100 patient-years (PY)) and TNFi-previous (653.6/100PY) than in TNFi-naive (551.1/100PY) patients. Serious AE rates were 18.0/100PY, 28.0/100PY and 18.6/100PY; serious infection rates were 6.0/100PY, 6.8/100PY and 4.2/100PY, respectively. At week 4, 36.5% of patients achieved ACR20 response and 14.9% DAS28 remission (<2.6); at week 24, 66.9%, 46.6%, 26.4% and 56.8% achieved ACR20/ACR50/ACR70 responses and DAS28 remission, respectively. Overall, 61.6% (TNFi-naive), 48.5% (TNFi-previous) and 50.4% (TNFi-recent) patients achieved DAS28 remission. CONCLUSIONS: In patients with RA who were DMARD-IR/TNFi-IR, tocilizumab ± DMARDs provided rapid and sustained efficacy without unexpected safety concerns.

The Role of Plasma Calprotectin in Non-infectious Uveitis.

PURPOSE: To investigate the role of plasma calprotectin in non-infectious uveitis. METHODS: This is an observational both cross-sectional and prospective study. Patients with active non-infectious uveitis were recruited as well as nonuveitic controls. Plasma calprotectin was determined and an ophthalmological examination was performed for both patients and controls. Independent variables possibly influencing levels of plasma calprotectin were recorded and analyzed. Categorical variables were compared by chi-square test (applying correction by continuity if necessary). T-test (or Kruskal-Wallis when appropriate) was used to compare averages. Multiple linear regression analysis was used to assess relationship between plasma calprotectin levels and independent variables. Spearman coefficient was calculated in order to establish correlation between plasma calprotectin and anterior chamber cell grading. Changes in plasma calprotectin levels between the flare beginning and its resolution were determined with mixed model for repeated measures. R software (version 3.6.0) was used to perform the statistical analysis. RESULTS: We included 74 patients and 40 controls in the cross-sectional study. Plasma calprotectin levels were higher in uveitis patients compared to those of controls (p = .003), being higher in younger patients and patients with posterior uveitis. No correlation between calprotectin and anterior chamber inflammation degree was found (p = .198). For the prospective study, we included 36 patients. We found no significant differences in calprotectin levels between active and inactive uveitis (p = .344). CONCLUSIONS: Plasma calprotectin levels are elevated in uveitis patients and are influenced by age and anatomical location of uveitis. Further investigation is needed to assess the relationship between calprotectin and uveitis activity.

Synthesis of water-soluble palladium(ii) complexes with N-heterocyclic carbene chelate ligands and their use in the aerobic oxidation of 1-phenylethanol.

The synthesis of palladium(ii) complexes containing N-heterocyclic carbene chelate ligands is reported. These chelate ligands have methylene or ethylene ring bridges and sulfonate, carbonate or ammonium functionalities to render the complexes soluble in water. Bis- [(bis-NHC)PdX2] (X = Cl, Br or I) and tetra-carbene [(bis-NHC)2Pd] complexes have been prepared and the crystal structures of two of them have been determined. The NHC ligand is coordinated to the metal center in normal (C2-bound) or abnormal (C4-bound) mode. Processes involving the formation of NHC-Pd bonds or the transfer of NHC ligands have been explored in water. The behavior of the bis-carbene complexes as catalysts for the aerobic oxidation of 1-phenylethanol is also discussed.

Magnetically recoverable catalysts based on mono- or bis-(NHC) complexes of palladium for the Suzuki-Miyaura reaction in aqueous media: two NHC-Pd linkages are better than one.

Pre-synthesized mono- and bis(NHC) palladium complexes have been grafted onto magnetic core/shell γ-Fe2O3/silica particles and tested as catalysts in model Suzuki-Miyaura coupling reactions. The bis(NHC) immobilized complex was found to be a robust catalyst that can operate under mild conditions in aqueous media, even for the activation of chloroarene, whereas the mono(NHC) counterpart rapidly deactivates. Moreover, it can be readily recovered by magnetic separation and reused many times, providing very high productivities, and with so low leaching of palladium that the crude products obtained contain ≤10 ppm Pd.

Enantioselective Synthesis of Optically Active Polymeric Homo- and Bimetallic Oxalate-Bridged Networks [M(2)(ox)(3)](n)().

The synthesis of the enantiomeric forms of the two- and three-dimensional polymers: {[NBu(4)][MnCr(ox)(3)]}(n)() (1) (Bu = n-butyl, ox = oxalate), {[M(bpy)(3))][LiCr(ox)(3)]}(n)() (M = Ni (2), Ru (4)) (bpy = 2,2'-bipyridine), {[M(bpy)(3))][Mn(2)(ox)(3)]}(n)() (M = Ni (3), Ru (5)) using resolved [Cr(ox)(3)](3)(-) and [M(bpy)(3)](2+) (M = Ni, Ru) species as chiral building blocks, and their structural characterization are reported. The optical activity of these systems arises from the helical chirality of the tris-chelated subunits with Delta or Lambda configurations. Bimetallic two-dimensional optically active network 1 results from the stacking of similar metallo-oxalate honeycomblike layers containing [Cr(ox)(3)](3)(-) units of the same chirality. The assembly of homochiral species leads to optically active three-dimensional 3-connected 10-gon nets 2-5. Solid state circular dichroism (CD) measurements demonstrate the enantiomeric character of the obtained polymers. Absolute configurations of the metal centers have been assigned according to circular dichroism and X-ray diffraction data. Enantiomerically pure single crystals of the two enantiomeric forms, {[Ru(Delta)(bpy)(3))][Li(Delta)Cr(Delta)(ox)(3)]H(2)O}(n)() (4Delta) and {[Ru(Lambda)(bpy)(3))][Li(Lambda)Cr(Lambda)(ox)(3)]H(2)O}(n)() (4Lambda), have been obtained and the structures determined by X-ray diffraction studies (crystals data: cubic system, space group P2(1)3, a (Å) = 15.293(8) (4Delta), 15.289(2) (4Lambda), Z = 4).

[Consensus on the Use of Rituximab in Rheumatoid Arthritis. A document with evidence-based recommendations. Grupo de Expertos en Rituximab. ]. / Consenso de uso de rituximab en artritis reumatoide. Un documento con recomendaciones basadas en la evidencia.

INTRODUCTION: Rituximab has been employed successfully for the treatment of Rheumatoid Arthritis (RA). However, its particular mechanism of action, as well as a lack of concrete guidelines for its management have generated doubts on its use. OBJECTIVE: To establish recommendations that facilitates the use of rituximab in common clinical practice. METHODS: In a first Delphi round, 9 expert rheumatologists got together to develop questions on those subjects generating most doubts on the efficacy and safety of the drug. These were adapted to perform a systematic review of the evidence, which was presented in a second meeting. Nominal groups were formed to respond to each question and give a recommendation. These recommendations were presented in a second Delphi round to a larger group of experts in rheumatology. Once again recommendations were discussed, modified and voted upon. Once approved, a vote on the degree of agreement for each recommendation was carried out. RESULTS: 17 recommendations were established, 10 regarding efficacy and 7 safety. All of the efficacy recommendations except 3 presented a good or moderate degree of evidence. Among the safety recommendations, 3 had a good or moderate degree of evidence while in the rest it was indirect, scarce or non-existent and a product of expert recommendation. The degree of agreement between experts was elevated for most of the recommendations. CONCLUSIONS: These recommendations attempt to clear doubts on the use of rituximab and establish guidelines for its use in daily practice. Efficacy recommendations have a high degree of evidence, allowing the clinician to be guided in therapeutic decisions. Safety recommendations have a lower degree of evidence.

Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: a randomized, double-blind, placebo-controlled study using acetaminophen as a side comparator.

OBJECTIVE: To assess the effects of the prescription formulation of glucosamine sulfate (1,500 mg administered once daily) on the symptoms of knee osteoarthritis (OA) during a 6-month treatment course. METHODS: Three hundred eighteen patients were enrolled in this randomized, placebo-controlled, double-blind trial in which acetaminophen, the currently preferred medication for symptomatic treatment of OA, was used as a side comparator. Patients were randomly assigned to receive oral glucosamine sulfate 1,500 mg once daily (n = 106), acetaminophen 3 gm/day (n = 108), or placebo (n = 104). The primary efficacy outcome measure was the change in the Lequesne index after 6 months. Secondary parameters included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and response according to the Osteoarthritis Research Society International criteria. These outcome measures were assessed using an intent-to-treat analysis. RESULTS: At baseline, the study patients had moderately severe OA symptoms (mean Lequesne index approximately 11 points). Glucosamine sulfate was more effective than placebo in improving the Lequesne score, with a final decrease of 3.1 points, versus 1.9 with placebo (difference between glucosamine sulfate and placebo -1.2 [95% confidence interval -2.3, -0.8]) (P = 0.032). The 2.7-point decrease with acetaminophen was not significantly different from that with placebo (difference -0.8 [95% confidence interval -1.9, 0.3]) (P = 0.18). Similar results were observed for the WOMAC. There were more responders to glucosamine sulfate (39.6%) and acetaminophen (33.3%) than to placebo (21.2%) (P = 0.004 and P = 0.047, respectively, versus placebo). Safety was good, and was comparable among groups. CONCLUSION: The findings of this study indicate that glucosamine sulfate at the oral once-daily dosage of 1,500 mg is more effective than placebo in treating knee OA symptoms. Although acetaminophen also had a higher responder rate compared with placebo, it failed to show significant effects on the algofunctional indexes.

Transfer hydrogenation processes to mu(3)-alkylidyne groups on the organotitanium oxide [Ti(3)Cp*O(3)].

The photochemical treatment of mu(3)-alkylidyne complexes [[TiCp*(mu-O)](3)(mu(3)-CR)] (R=H (1), Me (2), Cp*=eta(5)-C(5)Me(5)) with the amines (2,6-Me(2)C(6)H(3))NH(2), Et(2)NH, and Ph(2)NH and the imine Ph(2)C=NH leads to the partial hydrogenation of the alkylidyne moiety that is supported on the organometallic oxide, [Ti(3)Cp*O(3)], and the formation of new oxoderivatives [[TiCp*(3)(mu-CHR)(R'NR")] (R"=2,6-Me(2)C(6)H(3), R'=H, R=H (3), Me (4); R'=R"=Et, R=H (5), Me (6); R'=R"=Ph, R=H (7), Me (8)) and [[TiCp*(mu-O)](3)(mu-CHR)(N=CPh(2))] (R=H (9), R=Me (10)), respectively. A sequential transfer hydrogenation process occurs when complex 1 is treated with tBuNH(2), which initially gives the mu-methylene [[TiCp*(mu-O)](3)(mu-CH(2))(HNtBu)] (11) complex and finally, the alkyl derivative [[TiCp*(mu-O)](3)(mu-NtBu)Me] (12). Furthermore, irradiation of solutions of the mu(3)-alkylidyne complexes 1 or 2 in the presence of diamines o-C(6)H(4)(NH(2))(2) and H(2)NCH(2)CH(2)NH(2) (en) affords [[TiCp*(mu-O)](3)(mu(3)-eta(2)-NC(6)H(4)NH)] (13) and [[TiCp*(mu-O)](3)(mu(3)-eta(2)-NC(2)H(4)NH)] (14) by either methane or ethane elimination, respectively. In the reaction of 1 with en, an intermediate complex [[TiCp*(mu-O)](3)(mu-CH(2))(NHCH(2)CH(2)NH(2))] (15) is detected by (1)H NMR spectroscopy. Thermal treatment of the complexes 4-10 quantitatively regenerates the starting mu(3)-alkylidyne compounds and the amine R'(2)NH or the imine Ph(2)C=NH; however, heating of solutions of 3 or 4 in [D(6)]benzene or a equimolecular mixture of both at 170 degrees C produces methane, ethane, or both, and the complex [[TiCp*(mu-O)](3)[mu(3)-eta(2)-NC(6)H(3)(Me)CH(2)]] (16). The molecular structure of 8 has been established by single-crystal X-ray analysis.