Associations of Resilience, Perceived Control of Health, and Depression with Geriatric Outcomes after Surgery.

OBJECTIVE: To identify if depression, resilience, and perceived control of health are related to 2.5-year mortality and instrumental activities of daily living (IADL) decline among older adults after surgery. SUMMARY BACKGROUND DATA: The relationships of psychosocial factors with postoperative mortality and IADL decline among older adults are understudied. METHODS: We identified 3778 community-dwelling older adults in the Health and Retirement Study (HRS) with Medicare claims for surgery (mean [SD] age: 75.4 [7.8] years, 53.9% women, and 86.0% non-Hispanic White). We assessed associations of depression, resilience, and perceived control of health with 2.5-year postoperative mortality and IADL decline using cox and modified Poisson regression analyses, adjusting for sociodemographic and health variables. RESULTS: The incidence of 2.5-year postoperative mortality was 18.5% and IADL decline was 9.4%. Depression was associated with a higher incidence and adjusted hazard [95% CI] of mortality (26% vs. 16%, aHR:1.2[0.9, 1.5]), but high resilience was associated with a lower incidence and adjusted hazard of mortality (9% vs. 21%, aHR:0.6[0.5, 0.8]). Those with depression had higher incidence and adjusted relative risk [95% CI] of IADL decline (17% vs. 7%, aRR:1.6[1.2, 2.2]), but lower incidence and adjusted relative risk of IADL decline was identified for those with high resilience (4% vs. 11%, aRR:0.6[0.4, 1.0]) and high perceived control of health (7% vs. 10%, aRR:0.6[0.4, 1.0]). CONCLUSION: While depression confers greater risk of mortality and IADL decline, higher resilience and perceived control of health may be protective. Addressing psychosocial factors in the peri-operative period may improve outcomes among older adults.

Damage clusters after gamma irradiation of a nanoparticulate plasmid DNA peptide condensate.

We have gamma-irradiated plasmid DNA in aqueous solution in the presence of submillimolar concentrations of the ligand tetra-arginine. Depending upon the ionic strength, under these conditions, the plasmid can adopt a highly compacted and aggregated form which attenuates by some two orders of magnitude the yield of damage produced by the indirect effect. The yields of DNA single- and double-strand breaks (SSB and DSB) which result are closely comparable with those produced in living cells. The radical lifetimes, diffusion distances, and track structure are expected to be similarly well reproduced. After irradiation, the aggregation was reversed by adjusting the ionic conditions. The approximate spatial distribution of the resulting DNA damage was then assayed by comparing the increases in the SSB and DSB yields produced by a subsequent incubation with limiting concentrations of the eukaryotic base excision repair enzymes formamidopyrimidine-DNA N-glycosylase (the FPG protein) and endonuclease III. Smaller increases in DSB yields were observed in the plasmid target that was irradiated in the condensed form. By modeling the spatial distribution of DNA damage, this result can be interpreted in terms of a greater extent of damage clustering.

DNA Binding Hydroxyl Radical Probes.

The hydroxyl radical is the primary mediator of DNA damage by the indirect effect of ionizing radiation. It is a powerful oxidizing agent produced by the radiolysis of water and is responsible for a significant fraction of the DNA damage associated with ionizing radiation. There is therefore an interest in the development of sensitive assays for its detection. The hydroxylation of aromatic groups to produce fluorescent products has been used for this purpose. We have examined four different chromophores which produce fluorescent products when hydroxylated. Of these, the coumarin system suffers from the fewest disadvantages. We have therefore examined its behavior when linked to a cationic peptide ligand designed to bind strongly to DNA.

Characterization of a lipophilic plasmid DNA condensate formed with a cationic peptide fatty acid conjugate.

In the presence of cationic ligands, DNA molecules can become aggregated into larger particles in a process known as condensation. DNA condensates are of interest as models for the dense packing found in naturally occurring structures such as phage heads and chromatin. They have found extensive application in DNA transfection and also provide convenient models with which to study DNA damage by the direct effect of ionizing radiation. Further, conjugates of cationic peptides with fatty acids may represent a class of attractive ligands for these areas because of their simple synthesis. When plasmid pUC18 is used as the DNA target and N-caproyl-penta-arginine amide (Cap-R(5)-NH(2)) is used as the ligand, the physical properties of the resulting mixtures were characterized using static and dynamic light scattering, sedimentation, dye exclusion, circular dichroism, nanoparticle tracking, and atomic force microscopy. Their chemical properties were assayed using solvent extraction and protection against hydroxyl radical attack and nuclease digestion. Titration of the plasmid with the Cap-R(5)-NH(2) ligand produced sharply defined changes in both chemical and physical properties, which was associated with the formation of condensed DNA particles in the 100-2000 nm size range. The caproyl group at the ligand's N-terminus produced a large increase in the partitioning of the resulting condensate from water into chloroform and in its binding to the neutral detergent Pluronic F-127. Both the physical and chemical data were all consistent with condensation of the plasmid by the ligand where the presence in the ligand of the caproyl group conferred an extensive lipophilic character upon the condensate.

Reduction of electron deficient guanine radical species in plasmid DNA by tyrosine derivatives.

Guanine bases are the most easily oxidized sites in DNA and therefore electron deficient guanine radical species are major intermediates in the direct effect of ionizing radiation (ionization of the DNA itself) on DNA as a consequence of hole migration to guanine. As a model for this process we have used gamma-irradiation in the presence of thiocyanate ions to generate single electron oxidized guanine radicals in a plasmid target in aqueous solution. The stable species formed from these radicals can be detected and quantified by the formation of strand breaks in the plasmid after a post-irradiation incubation using a suitable enzyme. If a tyrosine derivative is also present during irradiation, the production of guanine oxidation products is decreased by electron transfer from tyrosine to the intermediate guanyl radical species. By using cationic tyrosine containing ligands we are able to observe this process when the tyrosine is electrostatically bound to the plasmid. The driving force dependence of this reaction was determined by comparing the reactivity of tyrosine with its 3-nitro analog. The results imply that the electron transfer reaction is coupled to a proton transfer. The experimental conditions used in this model system provide a reasonable approximation to those involved in the radioprotection of DNA by tightly bound proteins in chromatin.

Structure reactivity relationship in the reaction of DNA guanyl radicals with hydroxybenzoates.

In DNA, guanine bases are the sites from which electrons are most easily removed. As a result of hole migration to this stable location on guanine, guanyl radicals are major intermediates in DNA damage produced by the direct effect of ionizing radiation (ionization of the DNA itself and not through the intermediacy of water radicals). We have modeled this process by employing gamma irradiation in the presence of thiocyanate ions, a method which also produces single electron oxidized guanyl radicals in plasmid DNA in aqueous solution. The stable products formed in DNA from these radicals are detected as strand breaks after incubation with the FPG protein. When a phenolic compound is present in solution during gamma irradiation, the formation of guanyl radical species is decreased by electron donation from the phenol to the guanyl radical. We have quantified the rate of this reaction for four different phenolic compounds bearing carboxylate substituents as proton acceptors. A comparison of the rates of these reactions with the redox strengths of the phenolic compounds reveals that salicylate reacts ca. 10-fold faster than its structural analogs. This observation is consistent with a reaction mechanism involving a proton coupled electron transfer, because intra-molecular transfer of a proton from the phenolic hydroxyl group to the carboxylate group is possible only in salicylate, and is favored by the strong 6-membered ring intra-molecular hydrogen bond in this compound.

Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis.

The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1, has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.

Radiation safety in the cardiac catheterization lab: A time series quality improvement initiative.

BACKGROUND: Interventional cardiologists have one of the highest annual radiation exposures yet systems of care that promote radiation safety in cardiac catheterization labs are lacking. This study sought to reduce the frequency of radiation exposure, for PCI procedures, above 1.5Gy in labs utilizing a Phillips system at our local institution by 40%, over a 12-month period. METHODS: We performed a time series study to assess the impact of different interventions on the frequency of radiation exposure above 1.5Gy. Process measures were percent of procedures where collimation and magnification were used and percent of completion of online educational modules. Balancing measures were the mean number of cases performed and mean fluoroscopy time. INTERVENTIONS: Information sessions, online modules, policies and posters were implemented followed by the introduction of a new lab with a novel software (AlluraClarity©) to reduce radiation dose. RESULTS: There was a significant reduction (91%, p<0.05) in the frequency of radiation exposure above 1.5Gy after utilizing a novel software (AlluraClarity©) in a new Phillips lab. Process measures of use of collimation (95.0% to 98.0%), use of magnification (20.0% to 14.0%) and completion of online modules (62%) helped track implementation. The mean number of cases performed and mean fluoroscopy time did not change significantly. CONCLUSION: While educational strategies had limited impact on reducing radiation exposure, implementing a novel software system provided the most effective means of reducing radiation exposure.

Use of a coumarin-labeled hexa-arginine peptide as a fluorescent hydroxyl radical probe in a nanoparticulate plasmid DNA condensate.

Coumarin derivatives have found application as probes for the hydroxyl radical because one of the products of the reaction between them is a highly fluorescent umbelliferone. We have examined the interaction in aqueous solution between a cationic coumarin-labeled hexa-arginine peptide ligand and plasmid DNA, and compared after gamma irradiation the yields of products derived from both of them. At low ionic strengths, the ligand binds very tightly to the plasmid. Compared with the structurally similar 4-methylumbelliferone (phenolic pK(a) = 7.8), the fluorescent product derived from gamma irradiation of the coumarin labeled cationic peptide is significantly more acidic (pK(a) = 6.1), making it a very convenient probe for solutions of pH in the physiological range. The yield of this product is generally in excellent agreement over a wide range of conditions with that of the single strand break product produced by the reaction of the hydroxyl radical with the plasmid. Thus coumarin-labeled peptide ligands offer promise as hydroxyl radical probes for locations in close proximity to DNA.

Characterization of condensed plasmid DNA models for studying the direct effect of ionizing radiation.

We have examined the changes in physical properties of aqueous solutions of the plasmid pUC18 that take place on the addition of the cationic oligopeptide penta-arginine. An increase in sedimentation rate and static light scattering, and changes in the nucleic acid CD spectrum all suggest that this ligand acts to condense the plasmid. Dynamic light scattering suggests the hydrodynamic radii of the condensate particles are a few micrometers, ca. 50-fold larger than that of the monomeric plasmid. Condensation of the plasmid also produces a ca. 100-fold decrease in the strand break yield produced by gamma irradiation. This extensive protection against reactive intermediates in the bulk of the solution implies that condensed plasmid DNA may offer a model system with which to study the direct effect of ionizing radiation (ionization of the DNA itself). The use of peptide ligands as condensing agents in this application is attractive because the derivatives of several amino acids (particularly tryptophan and tyrosine) have been shown to modify the radiation chemistry of DNA extensively.