Modulation of endogenous antioxidant defense and the progression of kidney disease in multi-heritage groups of patients with type 2 diabetes: PRospective EValuation of Early Nephropathy and its Treatment (PREVENT).

BACKGROUND: Diabetes is the western world's leading cause of end-stage renal disease. Glucose-dependent, oxidative stress is linked to the development of renal inflammation and sclerosis, which, in animal models of diabetes, can be prevented by anti-oxidative treatment. Patients of non-Caucasian heritage have low activity of the selenoprotein, antioxidant enzyme, glutathione peroxidase (GPx) and its co-factor vitamin E, which may be linked to their increased propensity to developing end-stage renal disease. RESEARCH DESIGN AND METHODS: We have designed a double-blind, randomized, placebo controlled study with selenium and/or vitamin E versus placebo as the interventions for patients with type 2 diabetes and chronic kidney disease (CKD) stages 1-3. A 2 × 2 factorial design will allow a balanced representation of the heritage groups exposed to each intervention. The primary biochemical outcome is change in GPx activity, and clinical outcome measure is the actual, rate of-and/or percentage change in estimated glomerular filtration rate (eGFR) from baseline. Analysis will be with a marginal model for longitudinal data using Generalized Estimating Equations corrected for measures of baseline serum antioxidant enzyme activities (GPx, superoxide dismutase and catalase), micronutrient levels (vitamins E and C), measures of inflammation (interleukin 6, c-reactive protein and monocyte chemoattractant protein-1) and markers of oxidative damage (plasma 8-isoprostaglandin F2α and urinary 8-hydroxydeoxyguanosine). EXPECTED RESULTS: The study will assess the relationship between GPx activity, oxidative stress, inflammation and eGFR. It will test the null hypothesis that antioxidant therapy does not influence the activity of GPx or other antioxidant enzymes and/or alter the rate of change in eGFR in these patient groups. CONCLUSIONS: Outcome data on the effect of antioxidants in human diabetic renal disease is limited. Previous post hoc analyses have not shown a beneficial effect of vitamin E on renal function. A recent trial of a pharmaceutical antioxidant agent, improved eGFR, but in patients with advanced diabetes-related chronic kidney disease its use was associated with an increased incidence of cardiovascular events. We will explore whether the nutritional antioxidants, vitamin E and selenium alone, or in combination in patients at high risk of renal disease progression, forestalls a reduction in eGFR. The study will describe whether endogenous antioxidant enzyme defenses can be safely modified by this intervention and how this is associated with changes in markers of oxidative stress. Trial registration ISRCTN 97358113. Registered 21st September 2009

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Configuration mixing in Mg 28 and the Mg 26 (t,p) Mg 28 reaction

We have studied the Mg26(t,p)Mg28 reaction. The nucleus Mg28 lies between Mg24 and Mg32, the latter of which is central to the "island of inversion"characterized by low-lying neutron fp-shell configurations. The present results show that the second-excited 0+ state in Mg28 contains large fp-shell occupation for the neutrons. The experiment was performed in inverse kinematics using the HELIcal Orbit Spectrometer (HELIOS) at Argonne National Laboratory. Shell-model calculations using the SDPF-MU interaction yielded level energies and two-neutron transfer amplitudes that were used in one-step distorted-wave Born approximation calculations to provide theoretical predictions of the proton angular distributions. In many, but not all cases, the data were in good agreement with theoretical predictions

Search for the 1/2+ intruder state in P 35

The excitation energy of deformed intruder states (specifically the 2p2h bandhead) as a function of proton number Z along N=20 is of interest both in terms of better understanding the evolution of nuclear structure between spherical Ca40 and the Island of Inversion nuclei, and for benchmarking theoretical descriptions in this region. At the center of the N=20 Island of Inversion, the npnh (where n=2,4,6) neutron excitations across a diminished N=20 gap result in deformed and collective ground states, as observed in Mg32. In heavier isotones, npnh excitations do not dominate in the ground states but are present in the relatively low-lying level schemes. With the aim of identifying the expected 2p2h - s1/2+ state in P35, the only N=20 isotone for which the neutron 2p2h excitation bandhead has not yet been identified, the S36(d,He3)P35 reaction has been revisited in inverse kinematics with the HELical Orbit Spectrometer (HELIOS) at the Argonne Tandem Linac Accelerator System (ATLAS). While a candidate state has not been located, an upper limit for the transfer reaction cross section to populate such a configuration within a 2.5 to 3.6 MeV energy range provides a stringent constraint on the wave function compositions in both S36 and P35

Search for the 1/2+ intruder state in P 35

The excitation energy of deformed intruder states (specifically the 2p2h bandhead) as a function of proton number Z along N=20 is of interest both in terms of better understanding the evolution of nuclear structure between spherical Ca40 and the Island of Inversion nuclei, and for benchmarking theoretical descriptions in this region. At the center of the N=20 Island of Inversion, the npnh (where n=2,4,6) neutron excitations across a diminished N=20 gap result in deformed and collective ground states, as observed in Mg32. In heavier isotones, npnh excitations do not dominate in the ground states but are present in the relatively low-lying level schemes. With the aim of identifying the expected 2p2h - s1/2+ state in P35, the only N=20 isotone for which the neutron 2p2h excitation bandhead has not yet been identified, the S36(d,He3)P35 reaction has been revisited in inverse kinematics with the HELical Orbit Spectrometer (HELIOS) at the Argonne Tandem Linac Accelerator System (ATLAS). While a candidate state has not been located, an upper limit for the transfer reaction cross section to populate such a configuration within a 2.5 to 3.6 MeV energy range provides a stringent constraint on the wave function compositions in both S36 and P35