Coenzyme Q10 dose-escalation study in hemodialysis patients: safety, tolerability, and effect on oxidative stress.

BackgroundCoenzyme Q10 (CoQ10) supplementation improves mitochondrial coupling of respiration to oxidative phosphorylation, decreases superoxide production in endothelial cells, and may improve functional cardiac capacity in patients with congestive heart failure. There are no studies evaluating the safety, tolerability and efficacy of varying doses of CoQ10 in chronic hemodialysis patients, a population subject to increased oxidative stress.MethodsWe performed a dose escalation study to test the hypothesis that CoQ10 therapy is safe, well-tolerated, and improves biomarkers of oxidative stress in patients receiving hemodialysis therapy. Plasma concentrations of F2-isoprostanes and isofurans were measured to assess systemic oxidative stress and plasma CoQ10 concentrations were measured to determine dose, concentration and response relationships.ResultsFifteen of the 20 subjects completed the entire dose escalation sequence. Mean CoQ10 levels increased in a linear fashion from 704 ± 286 ng/mL at baseline to 4033 ± 1637 ng/mL, and plasma isofuran concentrations decreased from 141 ± 67.5 pg/mL at baseline to 72.2 ± 37.5 pg/mL at the completion of the study (P = 0.003 vs. baseline and P < 0.001 for the effect of dose escalation on isofurans). Plasma F2-isoprostane concentrations did not change during the study.ConclusionsCoQ10 supplementation at doses as high as 1800 mg per day was safe in all subjects and well-tolerated in most. Short-term daily CoQ10 supplementation decreased plasma isofuran concentrations in a dose dependent manner. CoQ10 supplementation may improve mitochondrial function and decrease oxidative stress in patients receiving hemodialysis.Trial registrationThis clinical trial was registered on clinicaltrials.gov [NCT00908297] on May 21, 2009

ABC-tool reinvented: development of a disease-specific 'Assessment of Burden of Chronic Conditions (ABCC)-tool' for multiple chronic conditions

BACKGROUND: Numerous instruments have been developed to assess patient reported outcomes; most approaches however focus on a single condition. With the increasing prevalence of multimorbidity, this might no longer be appropriate. Moreover, a more comprehensive approach that facilitates shared decision making and stimulates self-management is most likely more valuable for clinical practice than a questionnaire alone. This study aims to transform the Assessment of Burden of Chronic Obstructive Pulmonary Disease (COPD) (ABC)-tool into the Assessment of Burden of Chronic Conditions (ABCC)-tool for COPD, asthma, and diabetes mellitus type 2 (DM2). The tool consists of a scale, a visualisation of the outcomes, and treatment advice. METHODS: Requirements for the tool were formulated. Questionnaires were developed based on a literature study of existing questionnaires, clinical guidelines, interviews with patients and healthcare providers, and input from an expert group. Cut-off points and treatment advice were determined to display the results and to provide practical recommendations. RESULTS: The ABCC-scale consists of a generic questionnaire and disease-specific questionnaires, which can be combined into a single individualized questionnaire for each patient. Results are displayed in one balloon chart, and each domain includes practical recommendations. CONCLUSIONS: The ABCC-tool is expected to facilitate conversations between a patient and a healthcare provider, and to help formulate treatment plans and care plans with personalised goals. By facilitating an integrated approach, this instrument can be applied in a variety of circumstances and disease combinations

Patient outcomes, patient experiences and process indicators associated with the routine use of patient-reported outcome measures (PROMs) in cancer care:a systematic review

Purpose In current cancer care, there is a growing debate about the value of using patient-reported outcome measures (PROMs) in daily clinical follow-up. A systematic review of the literature was conducted to assess the evidence of the effectiveness of the routine use of PROMs in daily cancer care in terms of patient outcomes, patient experiences and process indicators and to identify the effect of giving feedback about PROM findings to patients and/or health care professionals (HCPs). Methods A systematic search was performed. Studies were eligible for inclusion when they (1) used a PROM as an intervention, with or without feedback to patients and/or HCPs, compared with not using a PROM, and (2) used a PROM as an intervention with feedback to patients and/or HCPs, compared with using a PROM without giving feedback to patients and/or HCPs. Results After screening of 8341 references, 22 original studies met the inclusion criteria. Most studies found a positive effect on survival, symptoms, HRQoL and patient satisfaction. In general, using feedback to patient and/or HCPs about the PROM results led to better symptom control, HRQoL, patient satisfaction and patient-doctor communication. The majority of included studies had insufficient power to detect significant differences in the outcomes assessed. Conclusion This review shows that predominantly positive findings were found in the use of a PROM in daily cancer care. Additionally, more positive effects were seen when feedback is provided to patient and/or health care professionals, and it is thus highly recommended that this is always done

CYP2D6 Mediates 4-Hydroxylation of Clonidine In Vitro: Implication for Pregnancy-Induced Changes in Clonidine Clearance

Clonidine is a centrally acting, α-2 adrenergic agonist used for the treatment of hypertension during pregnancy. The metabolic pathways of clonidine are poorly understood, and the quantitative contribution of specific human cytochrome P450 (P450) isoforms has not been systematically assessed. In this study, 17 cDNA-expressed P450 enzymes, in addition to pooled human liver microsomes, were evaluated for clonidine 4-hydroxylation activity in vitro. Five P450 enzymes—CYP2D6, 1A2, 3A4, 1A1, and 3A5—catalyzed measurable formation of 4-hydroxyclonidine. Selective inhibition studies in human liver microsomes confirmed that these isoforms are jointly responsible for 4-hydroxylation of clonidine in vitro, and CYP2D6 accounted for approximately two-thirds of the activity. The major role of CYP2D6 in clonidine metabolism might explain the increase in its nonrenal clearance during pregnancy

Financing the clean development mechanism through debt-for-efficiency swaps? Case study evidence from a Uruguayan wind farm project

As one of Kyoto’s three flexibility mechanisms, the Clean Development Mechanism (CDM) allows the issuance of Certified Emission Reduction credits from offset projects in non-Annex I countries. As little attention has been paid to how CDM projects are financed, this article assesses whether offset schemes with public bodies should utilise debt swaps as a form of funding. Specifically, we examine whether a debt-for-efficiency swap between Uruguay and Spain within a wind power project increased project finance and generated greater development co-benefits. We assess the transaction using a simple evaluative framework: whether it delivered additional resources to the debtor country and/or government budget; whether it delivered more resources for climate change mitigation; whether it had a sizeable effect on overall debt burdens (creating ‘indirect’ benefits); and whether it aligned with government policy and systems (elements of the new aid approach). We find evidence that cautions against using the Spanish–Uruguayan case as a model for future debt-for-efficiency swaps

The role of hyperglycemia, insulin resistance, and blood pressure in diabetes-associated differences in cognitive performance - The Maastricht study

OBJECTIVE To study to what extent differences in cognitive performance between individuals with different glucose metabolism status are potentially attributable to hyperglycemia, insulin resistance, and blood pressure-related variables. RESEARCH DESIGN AND METHODS We used cross-sectional data from 2,531 participants from the Maastricht Study (mean age6 SD, 60 6 8 years; 52% men; n = 666 with type 2 diabetes), all of whom completed a neuropsychological test battery. Hyperglycemiawas assessed by a composite index of fasting glucose, postload glucose, glycated hemoglobin (HbA1c), and tissue advanced glycation end products; insulin resistance by the HOMA of insulin resistance index; and blood pressure-related variables included 24-h ambulatory pressures, their weighted SDs, and the use of antihypertensive medication. Linear regression analyses were used to estimate mediating effects. RESULTS After adjustment for age, sex, and education, individuals with type 2 diabetes, compared with those with normal glucose metabolism, performed worse in all cognitive domains (mean differences in composite z scores for memory -0.087, processing speed -0.196, executive function and attention -0.182; P values <0.032), whereas individuals with prediabetes did not. Diabetes-associated differences in processing speed and executive function and attention were largely explained by hyperglycemia (mediating effect 79.6% [bootstrapped 95% CI 36.6; 123.4] and 50.3% [0.6; 101.2], respectively) and, for processing speed, to a lesser extent by blood pressure-related variables (17.7% [5.6; 30.1]), but not by insulin resistance. None of the factors explained the differences in memory function. CONCLUSIONS Our cross-sectional data suggest that early glycemic and blood pressure control, perhaps even in the prediabetic stage, may be promising therapeutic targets for the prevention of diabetes-associated decrements in cognitive performance

The role of hyperglycemia, insulin resistance, and blood pressure in diabetes-associated differences in cognitive performance - The Maastricht study

OBJECTIVE To study to what extent differences in cognitive performance between individuals with different glucose metabolism status are potentially attributable to hyperglycemia, insulin resistance, and blood pressure-related variables. RESEARCH DESIGN AND METHODS We used cross-sectional data from 2,531 participants from the Maastricht Study (mean age6 SD, 60 6 8 years; 52% men; n = 666 with type 2 diabetes), all of whom completed a neuropsychological test battery. Hyperglycemiawas assessed by a composite index of fasting glucose, postload glucose, glycated hemoglobin (HbA1c), and tissue advanced glycation end products; insulin resistance by the HOMA of insulin resistance index; and blood pressure-related variables included 24-h ambulatory pressures, their weighted SDs, and the use of antihypertensive medication. Linear regression analyses were used to estimate mediating effects. RESULTS After adjustment for age, sex, and education, individuals with type 2 diabetes, compared with those with normal glucose metabolism, performed worse in all cognitive domains (mean differences in composite z scores for memory -0.087, processing speed -0.196, executive function and attention -0.182; P values <0.032), whereas individuals with prediabetes did not. Diabetes-associated differences in processing speed and executive function and attention were largely explained by hyperglycemia (mediating effect 79.6% [bootstrapped 95% CI 36.6; 123.4] and 50.3% [0.6; 101.2], respectively) and, for processing speed, to a lesser extent by blood pressure-related variables (17.7% [5.6; 30.1]), but not by insulin resistance. None of the factors explained the differences in memory function. CONCLUSIONS Our cross-sectional data suggest that early glycemic and blood pressure control, perhaps even in the prediabetic stage, may be promising therapeutic targets for the prevention of diabetes-associated decrements in cognitive performance

Coenzyme Q10 dose-escalation study in hemodialysis patients: safety, tolerability, and effect on oxidative stress

BACKGROUND: Coenzyme Q(10) (CoQ(10)) supplementation improves mitochondrial coupling of respiration to oxidative phosphorylation, decreases superoxide production in endothelial cells, and may improve functional cardiac capacity in patients with congestive heart failure. There are no studies evaluating the safety, tolerability and efficacy of varying doses of CoQ(10) in chronic hemodialysis patients, a population subject to increased oxidative stress. METHODS: We performed a dose escalation study to test the hypothesis that CoQ(10) therapy is safe, well-tolerated, and improves biomarkers of oxidative stress in patients receiving hemodialysis therapy. Plasma concentrations of F(2)-isoprostanes and isofurans were measured to assess systemic oxidative stress and plasma CoQ(10) concentrations were measured to determine dose, concentration and response relationships. RESULTS: Fifteen of the 20 subjects completed the entire dose escalation sequence. Mean CoQ(10) levels increased in a linear fashion from 704 ± 286 ng/mL at baseline to 4033 ± 1637 ng/mL, and plasma isofuran concentrations decreased from 141 ± 67.5 pg/mL at baseline to 72.2 ± 37.5 pg/mL at the completion of the study (P = 0.003 vs. baseline and P < 0.001 for the effect of dose escalation on isofurans). Plasma F(2)-isoprostane concentrations did not change during the study. CONCLUSIONS: CoQ(10) supplementation at doses as high as 1800 mg per day was safe in all subjects and well-tolerated in most. Short-term daily CoQ(10) supplementation decreased plasma isofuran concentrations in a dose dependent manner. CoQ(10) supplementation may improve mitochondrial function and decrease oxidative stress in patients receiving hemodialysis. TRIAL REGISTRATION: This clinical trial was registered on clinicaltrials.gov [NCT00908297] on May 21, 2009

Opportunities and limitations of in-gas-cell laser spectroscopy of the heaviest elements with RADRIS

International audienceThe radiation detection resonance ionization spectroscopy (RADRIS) technique enables laser spectroscopic investigations of the heaviest elements which are produced in atom-at-a-time quantities from fusion-evaporation reactions. To achieve a high efficiency, laser spectroscopy is performed in a buffer-gas environment used to thermalize and stop the high-energy evaporation residues behind the velocity filter SHIP. The required cyclic measurement procedure in combination with the applied filament collection for neutralization as well as confinement of the stopped ions and subsequent pulse-heat desorption constrains the applicability of the technique. Here, some of these limitations and also opportunities that arise from this unique measurement setup will be evaluated