Aims Both mitochondria and nitric oxide (NO•) contribute to cardioprotection by ischaemic preconditioning (IPC). IPC causes mild uncoupling of mitochondria via uncoupling proteins (UCPs) and the ...adenine nucleotide translocase (ANT), and mild uncoupling per se is cardioprotective. Although electrophilic lipids are known to activate mitochondrial uncoupling, the role of such species in IPC-induced uncoupling and cardioprotection is unclear. We hypothesized that endogenous formation of NO•-derived electrophilic lipids (nitroalkenes such as nitro-linoleate, LNO2) during IPC may stimulate mitochondrial uncoupling via post-translational modification of UCPs and ANT, thus affording cardioprotection. Methods Hearts from male Sprague-Dawley rats were Langendorff-perfused and subjected to IPC. Nitroalkene formation was measured by HPLC-ESI-MS/MS. The effects of exogenous LNO2 and biotin-tagged LNO2 on isolated heart mitochondria and cardiomyocytes were also investigated. Results Nitroalkenes including LNO2 were endogenously generated in mitochondria of IPC hearts. Synthetic LNO2 (<1 µM) activated mild uncoupling, an effect blocked by UCP and ANT inhibitors. LNO2 (<1 µM) also protected cardiomyocytes against simulated ischaemia–reperfusion injury. Biotinylated LNO2 covalently modified ANT thiols and possibly UCP-2. No effects of LNO2 were attributable to NO• release, cGMP signalling, mitochondrial KATP channels, or protective kinase signalling. Conclusion Components of a novel signalling pathway are inferred, wherein nitroalkenes formed by IPC-stimulated nitration reactions may induce mild mitochondrial uncoupling via post-translational modification of ANT and UCP-2, subsequently conferring resistance to ischaemia–reperfusion injury.
A study was performed on the optical defect centers and surface morphology of isotopically enriched layers grown on diamond anvils by microwave plasma chemical vapor deposition for applications as ...designer diamond anvils in high-pressure diamond anvil cell devices. Various mixtures of methane isotopes were used to grow homoepitaxial diamond with 13 C molar fractions of 0.01, 0.41, 0.83, and 0.99 as determined from Raman spectroscopy. Defect centers were studied at temperatures between 80 K and 320 K using micro-photoluminescence spectroscopy with an argon ion and krypton laser excitation source. The defect spectra were dominated by zero phonon lines (ZPL) from nitrogen-related defect centers at nominal energies of 1.945 eV (640 nm defect) and 2.156 eV (575 nm defect), especially for the non-(100) surfaces. Polished (100) surfaces fluoresced weakly. ZPLs at 1.77 eV and 1.68 eV were observed, but not for all isotopically mixed samples. The 1.77 eV ZPL appeared to be associated with the original diamonds, while the 1.68 eV ZPL is known to originate with silicon-based defects. Atomic force microscopy (AFM) of as-grown isotopically enriched layers showed rough growth steps in areas with surface roughness of 100 nm and smooth areas with surface roughness of a few nanometers. This study indicates that (100) polished surfaces of isotopically enriched designer diamonds with low concentration of nitrogen defect centers can be fabricated for a variety of applications in high pressure research. A separate study was performed on the growth of large crystals by chemical vapor deposition. These experiments included the effect of methane concentration, oxygen addition, and nitrogen addition on the growth rate and surface morphology. It was found that the largest impact on the surface morphology was the microwave power density, which changed the surface from a hillock-type growth to a step-flow growth. The surface defects were studied using an AFM and optical imaging, while the optical defects were analyzed using photoluminescence spectrometry. A crystal of 3mm in size was grown in a period of 60 hours.
A core question in evolutionary biology is whether convergent phenotypic evolution is driven by convergent molecular changes in proteins or regulatory regions. We combined phylogenomic, ...developmental, and epigenomic analysis of 11 new genomes of paleognathous birds, including an extinct moa, to show that convergent evolution of regulatory regions, more so than protein-coding genes, is prevalent among developmental pathways associated with independent losses of flight. A Bayesian analysis of 284,001 conserved noncoding elements, 60,665 of which are corroborated as enhancers by open chromatin states during development, identified 2355 independent accelerations along lineages of flightless paleognaths, with functional consequences for driving gene expression in the developing forelimb. Our results suggest that the genomic landscape associated with morphological convergence in ratites has a substantial shared regulatory component.
Greater body mass index (BMI) has been associated with less radiographic progression in rheumatoid arthritis (RA). We evaluated the association between BMI and joint damage progression as measured by ...X-ray and MRI.
1068 subjects with RA from two clinical trials of golimumab (GO-BEFORE and GO-FORWARD) had radiographs performed at weeks 0, 52 and 104 and evaluated using the van der Heijde-Sharp (vdHS) scoring system. Contrast-enhanced MRIs of the dominant wrist and hand were obtained at weeks 0, 12, 24, 52 and 104. Multivariable logistic regression evaluated the risk of radiographic progression for each BMI category (<25, 25-30, >30 kg/m(2)). Within GO-BEFORE, piecewise, robust generalised estimating equations marginal models assessed the probability of MRI erosion progression for each BMI category. Multivariable linear regression models assessed baseline associations between BMI and bone oedema (a precursor of bone erosion).
Higher BMI category was associated with a lower probability of progression in vdHS score at weeks 52 and 104 independent of potential confounders. Higher BMI was also independently associated with a lower probability of progression in MRI erosion score over 2 years. Subjects with greater BMI demonstrated less bone oedema independent of differences in other disease severity measures, including MRI synovitis in the same joints.
Greater BMI is associated with a lower risk of progression on X-ray and MRI over 2 years. Subjects with greater BMI also demonstrate less bone oedema at baseline. Greater BMI may indicate a less aggressive RA phenotype and aid in risk stratification.
We report the results of a long-term follow-up of subjects in a phase 1 study of AAV2-hAADC (adeno-associated virus type 2-human aromatic L-amino acid decarboxylase) gene therapy for the treatment of ...Parkinson's disease (PD). Ten patients with moderately advanced PD received bilateral putaminal infusions of either a low or a high dose of AAV2-hAADC vector. An annual positron emission tomography (PET) imaging with (18)Ffluoro-L-m-tyrosine tracer was used for evaluation of AADC expression, and a standard clinical rating scale Unified Parkinson's Disease Rating Scale (UPDRS) was used to assess effect. Our previous analysis of the 6-month data suggested that this treatment was acutely safe and well tolerated. We found that the elevated PET signal observed in the first 12 months persisted over 4 years in both dose groups. A significantly increased PET value compared with the presurgery baseline was maintained over the 4-year monitoring period. The UPDRS in all patients off medication for 12 hr improved in the first 12 months, but displayed a slow deterioration in subsequent years. This analysis demonstrates that apparent efficacy continues through later years with an acceptable safety profile. These data indicate stable transgene expression over 4 years after vector delivery and continued safety, but emphasize the need for a controlled efficacy trial and the use of a higher vector dose.
Background: Distal biceps tendon repairs are commonly performed using open techniques. A minimally invasive distal biceps tendon repair technique using a speculum and hooded endoscope was developed ...to improve visualization, reduce soft-tissue dissection, and minimize complications. This paper describes the technique and reports the outcomes of 75 minimally invasive distal biceps tendon repairs. Methods: The operation reports and outcomes of 75 patients who underwent distal biceps tendon repair using this technique between 2011 and 2021 were retrospectively reviewed. Results: Median time to follow-up was 12 months (interquartile range IQR, 6-56 months). Primary outcomes were function as measured by the Disabilities of Arm, Shoulder and Hand Score (DASH) questionnaire, and rate of complications. Median DASH score was 1.7 of 100 (IQR, 0-6.8). There were 2 of 75 (2.7%) re-ruptures of the distal tendon. There were no cases of vascular injury, proximal radius fracture, or posterior interosseous nerve, median, or ulnar nerve palsy. Conclusions: In this series, minimally invasive distal biceps repair was safe and effective with a low rate of major complications. Recovery of function, as indicated by low DASH scores, was satisfactory, and inconvenience during recovery was minimized. Level of evidence: IV.
The disposition of vorinostat, an anticancer agent, was investigated in rats and dogs. Vorinostat possessed high serum clearance, a short elimination half-life and low oral bioavailability in both ...species. The renal route played an important role in the elimination of drug-related material and vorinostat was eliminated primarily by metabolic biotransformation.
Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma.
In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 ...patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebo group). The primary end point was progression-free survival.
Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups.
The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.).
Nitroalkene derivatives of linoleic acid (nitrolinoleic acid, LNO2) are formed via nitric oxide-dependent oxidative inflammatory reactions and are found at concentrations of ≈500 nM in the blood of ...healthy individuals. We report that LNO2is a potent endogenous ligand for peroxisome proliferator-activated receptor γ (PPARγ; Ki≈133 nM) that acts within physiological concentration ranges. This nuclear hormone receptor (PPARγ) regulates glucose homeostasis, lipid metabolism, and inflammation. PPARγ ligand activity is specific for LNO2and not mediated by LNO2decay products, NO donors, linoleic acid (LA), or oxidized LA. LNO2is a significantly more robust PPARγ ligand than other reported endogenous PPARγ ligands, including lysophosphatidic acid (16:0 and 18:1), 15-deoxy-Δ12,14- PGJ2, conjugated LA and azelaoyl-phosphocholine. LNO2activation of PPARγ via CV-1 cell luciferase reporter gene expression analysis revealed a ligand activity that rivals or exceeds synthetic PPARγ agonists such as rosiglitazone and ciglitazone, is coactivated by 9 cis-retinoic acid and is inhibited by the PPARγ antagonist GW9662. LNO2induces PPARγ-dependent macrophage CD-36 expression, adipocyte differentiation, and glucose uptake also at a potency rivaling thiazolidinediones. These observations reveal that NO-mediated cell signaling reactions can be transduced by fatty acid nitration products and PPAR-dependent gene expression.
PDF
