| 1. |
- Packer, M., et al.
(author)
-
Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure
- 2015
-
In: Circulation. - 0009-7322. ; 131, s. 54-61
-
Journal article (peer-reviewed)abstract
- BACKGROUND: -Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. METHODS AND RESULTS: -We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensinconverting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-Btype natriuretic peptide and troponin) versus enalapril. CONCLUSIONS: -Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.
|
|
| 2. |
- Godoy, Patricio, et al.
(author)
-
Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME
- 2013
-
In: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 87:8, s. 1315-1530
-
Research review (peer-reviewed)abstract
- This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4 alpha, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4 alpha), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
|
|
| 3. |
- McMurray, J. J., et al.
(author)
-
Resource utilization and costs in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme
- 2006
-
In: European heart journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 27:12, s. 1447-58
-
Journal article (peer-reviewed)abstract
- AIMS: More treatments are needed to improve clinical outcomes in chronic heart failure (HF). It is, however, important that treatments for a condition as common as HF are affordable. We have carried out a prospective economic analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. METHODS AND RESULTS: Patients with NYHA class II-IV HF and LVEF < or =0.40 were randomized to CHARM-Alternative if intolerant of an ACE-inhibitor or to CHARM-Added if taking an ACE-inhibitor. Patients with a LVEF >0.40 were randomized in CHARM-Preserved. Each trial compared the effect of candesartan to placebo on the primary outcome of cardiovascular death or HF hospitalization. Detailed information was prospectively collected on hospital admissions, procedures/operations and drugs. A cost-consequence analysis was performed for France, Germany and the UK for CHARM-Overall and a cost-effectiveness analysis for the low LVEF trials. The cost of candesartan was substantially offset by a reduction in hospital admissions, especially for HF. In the cost-consequence analysis, candesartan was cost-saving in most scenarios for CHARM-Alternative and Added but the marginal annual net cost per patient was upto 372 euros per year in CHARM-Preserved, in which candesartan did not reduce the primary outcome significantly. In the cost-effectiveness analysis of patients with a LVEF < or = 0.40, candesartan was cost-saving in some scenarios and in the others the maximum cost per life year gained was 3881 euros. CONCLUSION: Candesartan improves functional class, reduces the risk of hospital admission, and increases survival in patients with a HF and a LVEF < or =0.40 at an acceptable cost.
|
|
| 4. |
- Goderis, Steven, et al.
(author)
-
Globally distributed iridium layer preserved within the Chicxulub impact structure
- 2021
-
In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:9
-
Journal article (peer-reviewed)abstract
- The Cretaceous-Paleogene (K-Pg) mass extinction is marked globally by elevated concentrations of iridium, emplaced by a hypervelocity impact event 66 million years ago. Here, we report new data from four independent laboratories that reveal a positive iridium anomaly within the peak-ring sequence of the Chicxulub impact structure, in drill core recovered by IODP-ICDP Expedition 364. The highest concentration of ultrafine meteoritic matter occurs in the post-impact sediments that cover the crater peak ring, just below the lowermost Danian pelagic limestone. Within years to decades after the impact event, this part of the Chicxulub impact basin returned to a relatively low-energy depositional environment, recording in unprecedented detail the recovery of life during the succeeding millennia. The iridium layer provides a key temporal horizon precisely linking Chicxulub to K-Pg boundary sections worldwide.
|
|
| 5. |
|
|
| 6. |
- Kjekshus, John, et al.
(author)
-
Rosuvastatin in older patients with systolic heart failure.
- 2007
-
In: The New England journal of medicine. - 1533-4406. ; 357:22, s. 2248-61
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Patients with systolic heart failure have generally been excluded from statin trials. Acute coronary events are uncommon in this population, and statins have theoretical risks in these patients. METHODS: A total of 5011 patients at least 60 years of age with New York Heart Association class II, III, or IV ischemic, systolic heart failure were randomly assigned to receive 10 mg of rosuvastatin or placebo per day. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included death from any cause, any coronary event, death from cardiovascular causes, and the number of hospitalizations. RESULTS: As compared with the placebo group, patients in the rosuvastatin group had decreased levels of low-density lipoprotein cholesterol (difference between groups, 45.0%; P<0.001) and of high-sensitivity C-reactive protein (difference between groups, 37.1%; P<0.001). During a median follow-up of 32.8 months, the primary outcome occurred in 692 patients in the rosuvastatin group and 732 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.83 to 1.02; P=0.12), and 728 patients and 759 patients, respectively, died (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.31). There were no significant differences between the two groups in the coronary outcome or death from cardiovascular causes. In a prespecified secondary analysis, there were fewer hospitalizations for cardiovascular causes in the rosuvastatin group (2193) than in the placebo group (2564) (P<0.001). No excessive episodes of muscle-related or other adverse events occurred in the rosuvastatin group. CONCLUSIONS: Rosuvastatin did not reduce the primary outcome or the number of deaths from any cause in older patients with systolic heart failure, although the drug did reduce the number of cardiovascular hospitalizations. The drug did not cause safety problems. (ClinicalTrials.gov number, NCT00206310.)
|
|
| 7. |
- Ulaszewska, Marynka M., et al.
(author)
-
Nutrimetabolomics: An Integrative Action for Metabolomic Analyses in Human Nutritional Studies
- 2019
-
In: Molecular Nutrition and Food Research. - : Wiley. - 1613-4125 .- 1613-4133. ; 63:1
-
Research review (peer-reviewed)abstract
- The life sciences are currently being transformed by an unprecedented wave of developments in molecular analysis, which include important advances in instrumental analysis as well as biocomputing. In light of the central role played by metabolism in nutrition, metabolomics is rapidly being established as a key analytical tool in human nutritional studies. Consequently, an increasing number of nutritionists integrate metabolomics into their study designs. Within this dynamic landscape, the potential of nutritional metabolomics (nutrimetabolomics) to be translated into a science, which can impact on health policies, still needs to be realized. A key element to reach this goal is the ability of the research community to join, to collectively make the best use of the potential offered by nutritional metabolomics. This article, therefore, provides a methodological description of nutritional metabolomics that reflects on the state-of-the-art techniques used in the laboratories of the Food Biomarker Alliance (funded by the European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL)) as well as points of reflections to harmonize this field. It is not intended to be exhaustive but rather to present a pragmatic guidance on metabolomic methodologies, providing readers with useful “tips and tricks” along the analytical workflow.
|
|
| 8. |
- Renson, V, et al.
(author)
-
Lead isotopic analysis within a multiproxy approach to trace pottery sources. The example of White Slip II sherds from Late Bronze Age sites in Cyprus and Syria.
- 2013
-
In: Applied Geochemistry. - : Elsevier BV. - 0883-2927 .- 1872-9134. ; 28, s. 220-234
-
Journal article (peer-reviewed)abstract
- Lead isotope analyses were carried out on fragments of White Slip II ware, a Late Bronze Age Cypriote pottery ware, and on raw materials possibly used for their production. Sherds originate from three Late Bronze Age sites (Hala Sultan Tekke and Sanidha in Cyprus and Minet el-Beida in Syria) and clays come from the surroundings of Sanidha, a production site for White Slip ware. X-ray fluorescence (XRF) and a Principal Component Analysis (PCA) are combined with Pb isotope analyses to further investigate the effectiveness of the latter method within a multiproxy approach for pottery provenance study. The pottery sherds from the three sites are compared between themselves and with potential raw material. Additional X-ray diffraction (XRD) and analyses using a scanning electron microscope (SEM) equipped with an energy dispersive X-ray detection (EDX) facility were performed on selected sherds and clays. This work confirms that the clay source used for pottery production in Sanidha derives from local weathered gabbro. It also shows that different origins can be proposed for White Slip II ware sherds from Hala Sultan Tekke and Minet el-Beida and that clays were prepared prior to White Slip II ware production. It finally confirms the effectiveness of Pb isotopes in tracing pottery provenance not only by comparing sherd assemblages but also by comparing sherds to potential raw materials. (C) 2012 Elsevier Ltd. All rights reserved.
|
|
| 9. |
- Suh, Hyun Gyu, et al.
(author)
-
Cellular dehydration acutely degrades mood mainly in women : A counterbalanced, crossover trial
- 2021
-
In: British Journal of Nutrition. - 0007-1145. ; 125:10, s. 1092-1100
-
Journal article (peer-reviewed)abstract
- It is unclear if mild-to-moderate dehydration independently affects mood without confounders like heat exposure or exercise. This study examined the acute effect of cellular dehydration on mood. Forty-nine adults (55 % female, age 39 (SD 8) years) were assigned to counterbalanced, crossover trials. Intracellular dehydration was induced with 2-h (0·1 ml/kg per min) 3 % hypertonic saline (HYPER) infusion or 0·9 % isotonic saline (ISO) as a control. Plasma osmolality increased in HYPER (pre 285 (SD 3), post 305 (SD 4) mmol/kg; P < 0·05) but remained unchanged in ISO (pre 285 (SD 3), post 288 (SD 3) mmol/kg; P > 0·05). Mood was assessed with the short version of the Profile of Mood States Questionnaire (POMS). The POMS sub-scale (confusion-bewilderment, depression-dejection, fatigue-inertia) increased in HYPER compared with ISO (P < 0·05). Total mood disturbance score (TMD) assessed by POMS increased from 10·3 (SD 0·9) to 16·6 (SD 1·7) in HYPER (P < 0·01), but not in ISO (P > 0·05). When TMD was stratified by sex, the increase in the HYPER trial was significant in females (P < 0·01) but not in males (P > 0·05). Following infusion, thirst and copeptin (surrogate for vasopressin) were also higher in females than in males (21·3 (SD 2·0), 14·1 (SD 1·4) pmol/l; P < 0·01) during HYPER. In conclusion, cellular dehydration acutely degraded specific aspects of mood mainly in women. The mechanisms underlying sex differences may be related to elevated thirst and vasopressin.
|
|
| 10. |
- Suh, HyunGyu, et al.
(author)
-
Hypertonic Saline Infusion Acutely Degrades Mood in Healthy Volunteers (P23-014-19)
- 2019
-
In: Current Development in Nutrition. - 2475-2991. ; 3:Suppl 1
-
Journal article (peer-reviewed)abstract
- Objectives: Mild and moderate dehydration adversely affect mood and cognitive function. During dehydration, hypertonic hypovolemia activates both osmo- and baro-receptors but it is not known which physiological pathway is associated with degraded mood state. This study examined the acute effect of osmoreceptor stimulation on mood.Methods: Sixty healthy adults (50% females, 30 ± 1 y; BMI: 26.9 ± 4.0 kg·m-2) were infused intravenously with 3.0% (HYPER) or 0.9% (ISO) NaCl for 2 h (0.1 ml·kg-1·min-1) using a counterbalanced, crossover design. Blood samples were collected every 30 minutes to measure plasma osmolality (POsm), copeptin (a surrogate marker of vasopressin), and renin-angiotensin-aldosterone system (RAAS) hormones. Mood was assessed with the short version of Profile of Mood State (POMS) questionnaire before and after the infusion.Results: POsm and copeptin increased from 286 ± 3 mmol·kg-1 to 305 ± 4 mmol·kg-1 and from 4.5 ± 3.7 pmol·L-1 to 20.4 ± 12.8 pmol·L-1, respectively in HYPER (P < 0.05), and were unchanged in ISO (P > 0.05). No hormonal differences were observed between trials for RAAS hormones (P > 0.05). During HYPER copeptin, following the 2-h infusion, was greater in females than in males (female: 23.4 ± 13.9 pmol·L-1, male: 17.4 ± 10.9 pmol·L-1; P < 0.05). The POMS total mood disturbance (TMD) score increased from 10.5 ± 0.9 to 16.5 ± 1.6 in HYPER (P < 0.05), but not in ISO (P > 0.05). Among POMS subscales, depression-dejection and fatigue-inertia increased in HYPER compared to ISO (P < 0.05). When TMD responses in the HYPER trial were analyzed with sex as a between-subjects factor, the increase was significant in females (pre: 10.2 ± 1.0, post: 18.6 ± 2.3; P < 0.001) but not in males (pre: 10.8 ± 1.4, post: 14.0 ± 2.0; P > 0.05). The confusion-bewilderment subscales and fatigue-inertia of the POMS were also elevated post HYPER in females (P < 0.05), but not in ISO (P > 0.05) in either sex.Conclusions: Hypertonic saline infusion acutely degrades mood state, and women appear to have a more pronounced response. The underlying mechanisms remain to be determined but may be related to higher copeptin levels in women.The study was registered at ClinicalTrials.gov as NCT02761434.Funding Sources: Danone Research.Supporting Tables Images and/or Graphs:
|
|
