Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of infliximab therapy in patients with rheumatoid arthritis

Objectives: To investigate the possible role of baseline plasma tumour necrosis factor alpha levels (baseline-TNF) on the clinical response to infliximab in patients with rheumatoid arthritis (RA). Methods: Patients with RA refractory to methotrexate received 3, 6, or 10 mg/kg of infliximab every 8 weeks, in a randomised, double-blind manner: the RISING study. Clinical response (disease activity score in 28 joints based on C-reactive protein or American College of Rheumatology core set) at week 54 and serum infliximab levels were compared in three patient groups with low, intermediate, or high baseline-TNF (TNF-low, TNF-int, or TNF-high). Results: In TNF-low patients, the clinical response to different doses of infliximab was comparable, whereas TNF-int patients exhibited a dose-dependent trend. In contrast, TNF-high patients (approximately 13% of the total patients) had a clinical response to 10 mg/kg significantly better than the response to 3 and 6 mg/kg of infliximab. In TNF-high patients, the median trough serum levels of infliximab were below the detection limit (<0.1 μg/ml) at 3 and 6 mg/kg but were greater than 2 μg/ml at 10 mg/kg, whereas the levels were approximately 1 μg/ml for each dosage group in TNF-low patients. Conclusion: In patients with RA, baseline-TNF is significantly associated with the clinical response to infliximab in patients with a high baseline-TNF. A higher dose of infliximab may be necessary in these patients, whereas lower doses of infliximab are sufficient for those with a low baseline-TNF. Baseline-TNF may be a useful measure for personalising the treatment of RA using infliximab

Discovery of soticlestat, a potent and selective inhibitor for cholesterol 24-hydroxylase (CH24H)

Cholesterol 24-hydroxylase (CH24H, CYP46A1), a brain-specific cytochrome P450 (CYP) family enzyme, plays a role in the homeostasis of brain cholesterol by converting cholesterol to 24S-hydroxycholesterol (24HC). Despite a wide range of potential of CH24H as a drug target, no potent and selective inhibitors have been identified. Here, we report on the structure-based drug design (SBDD) of novel 4-arylpyridine derivatives based on the X-ray co-crystal structure of hit derivative 1b. Optimization of 4-arylpyridine derivatives led us to identify 3v ((4-benzyl-4-hydroxypiperidin-1-yl)­(2,4′-bipyridin-3-yl)­methanone, IC50 = 7.4 nM) as a highly potent, selective, and brain-penetrant CH24H inhibitor. Following oral administration to mice, 3v resulted in a dose-dependent reduction of 24HC levels in the brain (1, 3, and 10 mg/kg). Compound 3v (soticlestat, also known as TAK-935) is currently under clinical investigation for the treatment of Dravet syndrome and Lennox-Gastaut syndrome as a novel drug class for epilepsies

Indices calculated by serum creatinine and cystatin C as predictors of liver damage, muscle strength and sarcopenia in liver disease

Serum creatinine (Cr)-based glomerular filtration rate (CrGFR) is overestimated in liver disease. The present study evaluated whether the difference in CrGFR and cystatin C (CysC) GFR (dGFR) is significant in liver disease. The Cr-to-CysC ratio and sarcopenia index (SI) have been reported to correlate with muscle volume. An estimated total body muscle mass with Cr, CysC and calculated body muscle mass (CBMM) has also been reported to correlate with muscle mass. The applicability of dGFR, SI and CBMM for liver disease were evaluated. A total of 313 patients with liver damage were evaluated for Child-Pugh score, albumin-bilirubin (ALBI) score, model for end-stage liver disease, fibrosis-4, Cr, CysC, Cr-based estimated GFR (CreGFR), CysCGFR and grip strength. Of the 313 patients, 199 were evaluated using cross-sectional computed tomography (CT) of the third lumbar vertebra to determine the skeletal muscle (SM) mass. dGFR, CBMM and SI were compared to liver damage, muscle strength and muscle mass. In the 313 patients, dGFR was correlated with age, ALBI and grip strength; CBMM was correlated with body mass index (BMI) and grip strength; and SI was correlated with BMI and grip strength. In patients evaluated with CT, the correlation coefficients for CBMM and SI with SM were 0.804 and 0.293, respectively. Thus, CBMM and SI were associated with sarcopenia. The relationship between dGFR and ALBI does not differ with different grades of CrGFR-based chronic kidney disease (CKD). dGFR is a marker of liver damage and muscle strength regardless of CKD. CBMM and SI are markers for sarcopenia in liver disease

Review on Superconducting Materials

Short review of the topical comprehension of the superconductor materials classes Cuprate High-Temperature Superconductors, other oxide superconductors, Iron-based Superconductors, Heavy-Fermion Superconductors, Nitride Superconductors, Organic and other Carbon-based Superconductors and Boride and Borocarbide Superconductors, featuring their present theoretical understanding and their aspects with respect to technical applications.Comment: A previous version of this article has been published in \" Applied Superconductivity: Handbook on Devices and Applications \", Wiley-VCH ISBN: 978-3-527-41209-9. The new extended and updated version will be published in \" Encyclopedia of Applied Physics \", Wiley-VC

Photocatalytic CO₂ Reduction to Formic Acid Using a Ru(II)–Re(I) Supramolecular Complex in an Aqueous Solution

In an aqueous solution, photophysical, photochemical, and photocatalytic abilities of a Ru­(II)–Re­(I) binuclear complex (<b>RuReCl</b>), of which Ru­(II) photosensitizer and Re­(I) catalyst units were connected with a bridging ligand, have been investigated in details. <b>RuReCl</b> could photocatalyze CO₂ reduction using ascorbate as an electron donor, even in an aqueous solution. The main product of the photocatalytic reaction was formic acid in the aqueous solution; this is very different in product distribution from that in a dimethylformamide (DMF) and triethanolamine (TEOA) mixed solution in which the main product was CO. A ¹³CO₂ labeling experiment clearly showed that formic acid was produced from CO₂. The turnover number and selectivity of the formic acid production were 25 and 83%, respectively. The quantum yield of the formic acid formation was 0.2%, which was much lower, compared to that in the DMF–TEOA mixed solution. Detail studies of the photochemical electron-transfer process showed back-electron transfer from the one-electron-reduced species (OERS) of the photosensitizer unit to an oxidized ascorbate efficiently proceeded, and this should be one of the main reasons why the photocatalytic efficiency was lower in the aqueous solution. In the aqueous solution, ligand substitution of the Ru­(II) photosensitizer unit proceeded during the photocatalytic reaction, which was a main deactivation process of the photocatalytic reaction. The product of the ligand substitution was a Ru­(II) bisdiimine complex or complexes with ascorbate as a ligand or ligands

Formation of Transition Alumina Dust around Asymptotic Giant Branch Stars: Condensation Experiments using Induction Thermal Plasma Systems

Mid-infrared spectroscopic observations of oxygen-rich asymptotic giant branch (AGB) stars show the common presence of dust species that have a broad feature at similar to 11-12 mu m. Chemically synthesized amorphous alumina (Al2O3) is widely accepted as the source of this emission, although it is not obvious that amorphous alumina can condense in circumstellar conditions. We performed condensation experiments of Al-Si-Mg-O and Mg-Al-O gases using induction thermal plasma systems, in which small particles condense from vapors with a steep temperature gradient. The condensates were analyzed using X-ray diffraction and Fourier transform infrared spectroscopy, and observed with a transmission electron microscope. The condensed nanoparticles from the Al and O gases were transition aluminas based on face-centered cubic (fcc) packed oxygen (delta- and lambda-alumina, and an unknown phase). The fcc oxygen frameworks were maintained in the condensed alumina containing small amounts of Mg and Si. Condensates from the gases of Al:Mg = 99:1 and 95:5 had delta- and gamma-alumina structures. Particles with lambda- and gamma-alumina structures formed from starting materials of Al:Si = 9:1 and Al:Si:Mg = 8:1:1, respectively. Amorphous silica-rich particles condensed from gases of Al/(Si+Al) < 0.75. The condensed transition alumina containing similar to 10% Si showed similar spectral shapes to the observed dust emission from the alumina-rich AGB star T Cep. Based on the present results, it is reasonable that the source of 11-12 mu m broad emission of alumina-rich stars is not amorphous alumina, but is transition alumina containing similar to 10% Si

Quantification of monoacylglycerol lipase and its occupancy by an exogenous ligand in rhesus monkey brains using [18F]T-401 and PET

Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase that cleaves monoacylglycerols into fatty acids and is a potential target for the novel treatment of CNS disorders related to the endocannabinoid system and neuroinflammation. We have developed [18F]T-401 as a selective Positron emission tomography (PET) imaging agent for MAGL. In this study, we determined an analytical method to quantify MAGL availability and its occupancy by an exogenous inhibitor in rhesus monkey brains using [18F]T-401-PET. In rhesus monkeys, regional time-activity curves were described well when using an extended 2-tissue compartment model that accommodated the formation of a radiometabolite in the brain. This model yielded reliable estimates of the total distribution volume (VT), and the rank order of VT was consistent with known regional activity of MAGL enzyme in primates. The pretreatment of monkeys with JW642 resulted in a dose-dependent reduction of [18F]T-401 retentions in the brain, and VT. Lassen\u27s graphical analysis indicated a VND of 0.69 mL/cm3 and a plasma JW642 concentration of 126 ng/mL for inhibiting the specific binding by 50%. [18F]T-401 and the method established can be used for quantification of MAGL in healthy brain and in disease conditions, and is suitable for evaluations of target engagement at cerebral MAG