Sylviane Darquy

Arginine-supplemented enteral nutrition in critically ill diabetic and obese rats: A dose-ranging study evaluating nutritional status and macrophage function

OBJECTIVE Critically ill diabetic and obese patients are at high risk of complications. Arginine availability is lowered in diabetes and in stress situations, yet arginine is necessary for immune response, mainly by its action through nitric oxide (NO). These facts argue for arginine-supplemented diets in critically ill patients. However, studies have raised concerns about possible adverse effects of such diets in intensive-care patients. We therefore analyzed the metabolic and immunologic effects of an arginine-enriched diet in stressed diabetic-obese rats. METHODS Zucker Diabetic Fatty rats (fa/fa) were made endotoxemic by an intraperitoneal injection of lipopolysaccharide and then fed 4-d enteral nutrition enriched with arginine (ARG group) or a non-essential amino acid mix (NEAA group). The two groups each were subdivided into three subgroups: the ARG subgroups received 0.5 g (ARG0.5), 2 g (ARG2), and 5 g (ARG5) of arginine per kilogram daily, and the NEAA groups were made isonitrogenous with the corresponding ARG subgroups (NEAA0.5, NEAA2, and NEAA5). Plasma and urinary biomarkers were measured. Cytokine and NO production levels and inducible NO synthase and arginase protein levels were determined from peritoneal macrophages. RESULTS The survival rate was lower in the ARG5 and NEAA5 subgroups than in all the other subgroups. The nitrogen balance was higher in the ARG5 group than in the NEAA5 group. Plasma triacylglycerol levels were lower in the ARG2 group than in the NEAA2 group. Interleukin-6, tumor necrosis factor-α, and NO production in the macrophages decreased and arginase-1 was upregulated in the ARG-treated rats. CONCLUSIONS In this model, mortality was increased by the nitrogen burden rather than by arginine per se. Arginine improved nitrogen balance and had an anti-inflammatory action on macrophages by regulating NO production, probably through arginase-1 expression.

Women’s participation in breast cancer screening in France – an ethical approach

BackgroundBreast cancer is a major public health challenge. Organized mammography screening (OS) is considered one way to reduce breast cancer mortality. EU recommendations prone mass deployment of OS, and back in 2004, France introduced a national OS programme for women aged 50–74 years. However, in 2012, participation rate was still just 52.7%, well short of the targeted 70% objective. In an effort to re-address the (in) efficiency of the programme, the French National Cancer Institute has drafted an expert-group review of the ethical issues surrounding breast cancer mammography screening.DiscussionPrompted by emerging debate over the efficiency of the screening scheme and its allied public information provision, we keynote the experts’ report based on analysis of epidemiological data and participation rate from the public health authorities. The low coverage of the OS scheme may be partly explained by the fact that a significant number of women undergo mammography outside OS and thus outside OS criteria. These findings call for further thinking on (i) the ethical principles of beneficence and non-malfeasance underpinning this public health initiative, (ii) the reasons behind women’s and professionals’ behavior, and (iii) the need to analyze how information provision to women and the doctor-patient relationship need to evolve in response to scientific controversy over the risks and benefits of conducting mammographic screening.SummaryThis work calls for a reappraisal of the provision of screening programme information. We advocate a move to integrate the points sparking debate over the efficiency of the screening scheme to guarantee full transparency. The perspective is to strengthen the respect for autonomy allowing women to make an informed choice in their decision on whether or not to participate.

Arginine or citrulline associated with a statin stimulates nitric oxide production in bovine aortic endothelial cells.

Nitric oxide (NO) is an antiatherogenic vasodilator synthesized from arginine and, indirectly, from citrulline through argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL). Hypercholesterolemia-induced atherosclerosis is usually treated by statins, which decrease cholesterolemia and increase endothelial NO synthase (eNOS) activity. Therefore, a treatment associating a statin with arginine or citrulline could be more efficient than statin alone. The aim of this study was to optimize NO production in bovine aortic endothelial cells (BAEC) by a combination of simvastatin with arginine or citrulline and to identify the molecular mechanisms involved. NO production was measured after stimulation of BAEC in different conditions (simvastatin 0 to 10 μM associated with arginine or citrulline 0 to 5 mM) after 24-hour incubation. Intracellular levels of specific proteins were evaluated by Western-Blot analysis, and mRNA levels of eNOS, iNOS, caveolin-1, ASS and ASL were assessed by RT-PCR. Simvastatin co-administrated with arginine or citrulline increased NO production, but at simvastatin 10 μM, 1 mM arginine-induced NO production was significantly (P < 0.01) higher than 1 mM citrulline-induced NO production. Simvastatin induced an increase in eNOS mRNA expression and protein levels in the presence of arginine or citrulline. ASS and ASL mRNA levels were increased by simvastatin, whereas a high substrate concentration (1 mM) strongly decreased ASL mRNA levels. Combining statin with arginine or citrulline increased NO production in endothelial cells by increasing eNOS protein levels. These results form a strong rationale to evaluate the potential utilization of these in atherosclerosis prevention and treatment.

Ethical management in the constitution of a European database for leukodystrophies rare diseases

BACKGROUND The EU LeukoTreat program aims to connect, enlarge and improve existing national databases for leukodystrophies (LDs) and other genetic diseases affecting the white matter of the brain. Ethical issues have been placed high on the agenda by pairing the participating LD expert research teams with experts in medical ethics and LD patient families and associations. The overarching goal is to apply core ethics principles to specific project needs and ensure patient rights and protection in research addressing the context of these rare diseases. AIM This paper looks at how ethical issues were identified and handled at project management level when setting up an ethics committee. METHODS Through a work performed as a co-construction between health professionals, ethics experts, and patient representatives, we expose the major ethical issues identified. RESULTS The committee acts as the forum for tackling specific issues tied to data sharing and patient participation: the thin line between care and research, the need for a charter establishing the commitments binding health professionals and the information items to be delivered. Ongoing feedback on the database, including delivering global results in a broad-audience format, emerged as a key recommendation. Information should be available to all patients in the partner countries developing the database and should be scaled to different patient profiles. CONCLUSION This work led to a number of recommendations for ensuring transparency and optimizing the partnership between scientists and patients.

Partnering with patients in translational oncology research: ethical approach

BackgroundThe research program CARPEM (cancer research and personalized medicine) brings together the expertise of researchers and hospital-based oncologists to develop translational research in the context of personalized or “precision” medicine for cancer. There is recognition that patient involvement can help to take into account their needs and priorities in the development of this emerging practice but there is currently no consensus about how this can be achieved. In this study, we developed an empirical ethical research action aiming to improve patient representatives’ involvement in the development of the translational research program together with health professionals. The aim is to promote common understanding and sharing of knowledge between all parties and to establish a long-term partnership integrating patient’s expectations.MethodsTwo distinct committees were settled in CARPEM: an “Expert Committee”, gathering healthcare and research professionals, and a “Patient Committee”, gathering patients and patient representatives. A multidisciplinary team trained in medical ethics research ensured communication between the two committees as well as analysis of discussions, minutes and outputs from all stakeholders.ResultsThe results highlight the efficiency of the transfer of knowledge between interested parties. Patient representatives and professionals were able to identify new ethical challenges and co-elaborate new procedures to gather information and consent forms for adapting to practices and recommendations developed during the process. Moreover, included patient representatives became full partners and participated in the transfer of knowledge to the public via conferences and publications.ConclusionsEmpirical ethical research based on a patient-centered approach could help in establishing a fair model for coordination and support actions during cancer research, striking a balance between the regulatory framework, researcher needs and patient expectations. Our approach addresses the concept of translational ethics as a way to handle the main remaining gap between combining care and research activities in the medical pathway and the existing framework.

Patient/family views on data sharing in rare diseases: study in the European LeukoTreat project.

The purpose of this study was to explore patient and family views on the sharing of their medical data in the context of compiling a European leukodystrophies database. A survey questionnaire was delivered with help from referral centers and the European Leukodystrophies Association, and the questionnaires returned were both quantitatively and qualitatively analyzed. This study found that patients/families were strongly in favor of participating. Patients/families hold great hope and trust in the development of this type of research. They have a strong need for information and transparency on database governance, the conditions framing access to data, all research conducted, partnerships with the pharmaceutical industry, and they also need access to results. Our findings bring ethics-driven arguments for a process combining initial broad consent with ongoing information. On both, we propose key item-deliverables to database participants.

Erratum to: Partnering with patients in translational oncology research: ethical approach

Background: The research program CARPEM (cancer research and personalized medicine) brings together the expertise of researchers and hospital‐based oncologists to develop translational research in the context of personal‐ ized or “precision” medicine for cancer. There is recognition that patient involvement can help to take into account their needs and priorities in the development of this emerging practice but there is currently no consensus about how this can be achieved. In this study, we developed an empirical ethical research action aiming to improve patient representatives’ involvement in the development of the translational research program together with health profes‐ sionals. The aim is to promote common understanding and sharing of knowledge between all parties and to establish a long‐term partnership integrating patient’s expectations. Methods: Two distinct committees were settled in CARPEM: an “Expert Committee”, gathering healthcare and research professionals, and a “Patient Committee”, gathering patients and patient representatives. A multidisciplinary team trained in medical ethics research ensured communication between the two committees as well as analysis of discussions, minutes and outputs from all stakeholders. Results: The results highlight the efficiency of the transfer of knowledge between interested parties. Patient repre‐ sentatives and professionals were able to identify new ethical challenges and co‐elaborate new procedures to gather information and consent forms for adapting to practices and recommendations developed during the process. Moreover, included patient representatives became full partners and participated in the transfer of knowledge to the public via conferences and publications. Conclusions: Empirical ethical research based on a patient‐centered approach could help in establishing a fair model for coordination and support actions during cancer research, striking a balance between the regulatory frame‐ work, researcher needs and patient expectations. Our approach addresses the concept of translational ethics as a way to handle the main remaining gap between combining care and research activities in the medical pathway and the