Gastroenteritis for holiday season

In metropolitan France last week, the incidence rate for cases of acute diarrhoea seen in general practice was estimated at 253 cases per 100,000 inhabitants, i.e. 160,000 new cases, higher than the previous week, and just below the epidemic threshold (269 cases per 100,000 inhabitants).

At regional level, the highest rates of incidence were found in Limousin, Provence-Alpes-Côte-d’Azur and Ile-de-France.

The Réseau Sentinelles (Sentinel Network): a collaboration between general practitioners and researchers

Since 1984, the French National Institute of Health and Medical Research (Inserm) and Pierre and Marie Curie University (University of Paris 6) have developed an information system based on a network of general practitioners in metropolitan France known as the Réseau Sentinelles (Sentinel Network). It has enabled the creation of large databases for several diseases, with descriptions of individual cases seen in general practice, for health surveillance and research purposes.
The Réseau Sentinelles is a network of 1,300 private general practitioners (i.e. 2.2% of all private GPs in metropolitan France), distributed throughout the French metropolitan territory, who contribute on a voluntary basis. Member physicians are known as “Sentinel physicians.”

For further information, visit the Réseau Sentinelles website


Blood group O associated with a lower risk of developing type 2 diabetes

Is there a relationship between blood group and the risk of developing type 2 diabetes? This is the question studied by Guy Fagherazzi and his collaborators from Joint Research Unit 1018, “Centre for Research in Epidemiology and Population Health” (Inserm/University Paris-Sud) at Gustave Roussy Institute. The analysis, carried out on 82,104 women from the E3N cohort who were monitored for 18 years, suggests for the first time that the risk of type 2 diabetes may be lower for individuals with blood group O than for those with blood groups A, B or AB.

These results are published in the journal Diabetologia.

Groupe sanguin 


Diabetes affects more than 382 million people worldwide, 90% of whom have type 2 diabetes. Approximately 4.6% of the French population is affected by this disease, and the figure continues to grow. Known risk factors are obesity, lack of physical inactivity, excessive caloric intake, smoking, hypertension and hypercholesterolaemia. The researchers believe that it is now crucial to identify new factors that will make it possible to understand this disease and thereby slow its development.

In this study, 82,104 French women from the E3N cohort were monitored for 18 years, between 1990 and 2008.

“We show, for the first time in such a large population, that women with blood group O—approximately 43% of French people presently have this group—have a lower risk of developing type 2 diabetes,” explains Guy Fagherazzi, an epidemiologist at Inserm.

More specifically, women with other blood groups had an increased risk of developing diabetes, going from 10% for group A, to 17% for group AB, and 21% for group B, compared with group O.

When the individual’s Rhesus factor was taken into account, the researchers noted that women with blood group O- (only 6% of the French population) had a lower risk of diabetes than the others.

How can these results be explained?

At present there are few biological mechanisms that make it possible to link blood group to the risk of type 2 diabetes, but some hypotheses already identified might partly explain the observed association:

  • It would seem that some endothelial markers and inflammatory markers are present in greater quantity in people who are not blood group O. And these markers are associated with an increased risk of type 2 diabetes.
  • ABO blood group has also been identified as being one of the genetically determined factors modulating the composition of the intestinal microbiota, which in turn plays a role in glucose metabolism, energy balance and chronic inflammation.

“Despite the robustness of our data, it is necessary to replicate this study in other large populations, especially populations with other genetic backgrounds, and in men, even though the mechanisms proposed are not sex-dependent,” says Guy Fagherazzi, first author of the study.

If these observations are confirmed, it might be relevant to collect blood group information in routine practice, in future studies regarding type 2 diabetes, and when monitoring people at risk. The researchers will need to determine why individuals with blood group O are at lower risk of developing type 2 diabetes.

THE E3N ( AND E4N ( studies

The E3N study, or Epidemiological Study (Etude) of women in MGEN (Mutuelle Générale de l’Education Nationale, a health insurance plan covering mostly teachers), headed by Françoise Clavel-Chapelon, Inserm Research Director, is a prospective cohort study of approximately 100,000 French women volunteers born between 1925 and 1950, and monitored since 1990.

Since 1990, women have completed and returned a self-administered questionnaire every 2-3 years. They are asked both about their lifestyle (diet, use of hormone treatments, etc.) and about changes in their state of health.

Data on risk factors have been the subject of several validation studies. The rate of “loss to follow-up” is very low, because MGEN offers the possibility of following up nonrespondents. However, it is mainly thanks to the loyalty and reliability of the participants and the collaboration of treating physicians that the E3N study can provide all these results.

The E3N study is supported by four founding partners: Inserm, the French National Cancer League, Gustave Roussy Institute and MGEN.

The E4N study has just been launched, and is aimed at extending the E3N study by monitoring family members of E3N women. Ultimately, E4N will include three generations: E3N women and the fathers of their children constitute the first generation; their children, the second; and their grandchildren will form the third generation. Monitoring the three generations will make it possible to collect information on behavioural and environmental factors at different periods of life. The main objective of the E4N study is to study health in relation to environment and modern lifestyle in subjects from the same family with a shared genetic background and environment.


A mechanism for eliminating proteins accidentally localised to the cell nucleus

An international collaboration coordinated by the German Cancer Research Center (DKFZ) (University of Heidelberg), including French researchers from the Institute of Genetics and Development of Rennes (IGDR) (CNRS/University of Rennes 1) under the leadership of Gwenaël Rabut, Inserm Researcher, and teams from Sweden and Canada, has just demonstrated a new molecular mechanism that may allow cells to destroy proteins accidentally localised to the nucleus.

This research is published in the journal Nature.

Biological processes are far from perfect. Despite millions of years of refinement, the molecular mechanisms that help living beings to function make many errors, which can have serious consequences unless they are detected and corrected. For example, many cancers are caused by errors that occur while our genetic material is being copied. Similarly, incorrect folding of some neuronal proteins leads to the formation of toxic aggregates that disrupt nervous system function and cause neurodegenerative diseases, such as Alzheimer’s disease or Parkinson’s disease.

To prevent this happening, cells have established complex molecular mechanisms that control the quality of proteins and eliminate those that are defective. These mechanisms are localised and implemented mainly in the cytoplasm (the cellular compartment where the proteins are synthesised).

While working on several factors involved in protein quality control, researchers discovered that some of them are also localised in the cell nucleus (the compartment that contains the genetic material), and that they enable the degradation of proteins that are abnormally present in this compartment.

During this study, researchers from the Institute of Genetics and Development of Rennes (including Gwenaël Rabut, Inserm Researcher, project coordinator and manager in Rennes, and Ewa Blaszczak, doctoral student, joint first author of the article) were able to observe that these factors involved in protein quality control interact with each other in the nucleus and bring about the ubiquitination (the step preceding degradation) of a protein accidentally localised to the nucleus.

By using an observation method developed at the University of Heidelberg, based on fluorescence timing in the proteins of interest, the researchers were able to identify some twenty proteins the degradation of which depended on quality control factors localised in the nucleus. Since several of these proteins are normally localised to the cytoplasm, and accumulate in the nucleus when they are no longer degraded, the researchers propose that this quality control system serves to eliminate not only defective proteins, but also proteins accidentally localised to the nucleus.

These discoveries were made using a model organism, baker’s yeast, but it is likely that similar mechanisms also exist in humans.

Valérie Mazeau-Woynar appointed Director of the Department of Partnerships and External Relations (DPRE) at Inserm

Valérie Mazeau-Woynar succeeds Claire Giry at the head of Inserm’s Department of Partnerships and External Relations (DPRE). In this role, she will contribute to the implementation of Inserm’s institutional partnerships at regional, national, European and international level, at the behest of Directorate General, and in coordination with the Thematic Institutes.

PhotoCP web

With her multidisciplinary background in medicine, biomedical research and public health policy, acquired in France and the United States, Valérie Mazeau-Woynar was previously Director of Recommendations and Quality of Expertise at the French National Cancer Institute (INCa). She coordinated the preparation of the 2014-2019 Cancer Control Plan, which defines France’s national strategy for action on cancer. Valérie Mazeau-Woynar has also authored or supervised over 60 reports published by that Institute between 2008 and 2014: national recommendations for specialist teams, guides for general practitioners, patient guides and scientific reports.

With extensive experience in institutional relations with central government and the health and research agencies, learned societies, patient associations and foundations, Valérie Mazeau-Woynar will now put her ability to analyse medical, scientific and strategic situations at the service of Inserm’s Department of Partnerships and External Relations.

“Given my strong commitment to helping improve population health, I am pleased and honoured to be joining Inserm, and using my skills in research that will make it possible to better prevent illnesses and improve the care of tomorrow’s patients.”
Valérie Mazeau-Woynar

In the course of her duties, she will contribute to promoting a site policy, developing institutional cooperation at regional, national, European and international level, and defining Inserm’s strategy with the Directorate General.

Improved understanding of the diabetic process via the Rfx6 gene

For the first time, the team led by Gérard Gradwohl, an Inserm Research Director at the Institute of Genetics and Molecular and Cellular Biology, Illkirch (IGBMC/Inserm-CNRS-University of Strasbourg), has shown that the Rfx6 gene is essential for the functioning of the cells that produce insulin, the pancreatic beta cells. In adult mice, this gene has proved important not only for allowing the secretion of insulin, but for also playing a major role in beta cell identity. As a logical progression of this work carried out in the rodent, the team led by Raphaël Scharfmann, an Inserm Research Director (Unit 106, “Cochin Institute”/Inserm-Paris Descartes University-CNRS) has confirmed these results in human pancreatic beta cells and in a 6 year old child with neonatal diabetes.
Both of these studies are published in the 11 December 2014 issue of the journal Cell Reports.

ilots langherans

Immunofluorescence, histological section of an islet of Langerhans from an adult mouse pancreas showing expression of Rfx6 transcription factor (red) in the β-cell nuclei (stained green with insulin) ©Julie Piccand 

In 2010, scientists provided evidence that the Rfx6 gene plays a key role in the formation of insulin-producing cells. In mice where this gene was mutated or deleted (absent), severe diabetes appeared at birth, resulting in death of the pups. In human newborns with mutations, neonatal diabetes is diagnosed very early, and then controlled with insulin treatment.

Among the factors involved in neonatal diabetes, Rfx6 is acquiring the status of an essential gene in the control of insulin secretion, and is therefore potentially involved in the diabetic process in adults. Indeed, researchers at IGBMC have created animal models in mice, in which the mature β-cells have been modified so as to inactivate their Rfx6 gene. The result: these mutant mice show glucose intolerance (prediabetes). By what mechanisms? Without Rfx6 expression in β-cells, several critical steps in glucose-induced insulin secretion are disrupted, such as glucose detection, electrical activity of the β-cells and calcium ion flux.

In fact, Rfx6 directly regulates the expression of key genes controlling these processes. This sequence of steps leads to the secretion of insulin according to fluctuations in blood sugar levels, and disruption of the steps causes defective insulin production.

Even more surprisingly, on examining the transcriptome of mutant mice (without Rfx6), Gérard Gradwohl’s team observed that genes that are normally repressed in β-cells become active. These genes, known as “disallowed,” are expressed instead of remaining silent. Their activation then leads to loss of β-cell identity. In a manner of speaking, they undergo dedifferentiation and “forget” their raison d’être and function.

Observations validated in humans

As a logical progression from this work carried out in the rodent, Raphaël Scharfmann’s team has confirmed the results for human β-cells. For 30 years, researchers throughout the world had been trying to reproduce these β-cells in the laboratory in order to study them and understand their dysfunction. In 2011, Raphaël Scharfmann and his academic and industrial collaborators from the EndoCells company were the first in the world to produce functional human β-cell lines in vitro. They therefore possessed the necessary “toolkit” to explore the role of Rfx6 in humans.

Moreover, their genetic analyses of children with neonatal diabetes had shown mutations in the Rfx6 gene, without their knowing what its role might be in the disease.

The researchers therefore sought to crack the Rfx6 mystery simultaneously in normal functional human β-cells, β-cells in which the Rfx6 gene was not expressed, and in a 6 year old child with neonatal diabetes.

Their studies show, like those of the researchers in Strasbourg, that Rfx6 plays a central role in controlling not only insulin production in β-cells, but also the secretion of insulin into the bloodstream.

More specifically, Rfx6 acts on the β-cell membrane by controlling the opening and closing of the Ca2+.(calcium) channels. Normally, glucose enters the pancreatic β-cell by facilitated diffusion. This entry causes a cascade of reactions that lead to the opening of the calcium channels that allow the release of insulin into the bloodstream. Where Rfx6 is mutated and nonfunctional, it prevents the opening of the Ca2+.channels, and blocks subsequent insulin secretion.

For the researchers, this work has three-fold value. It confirms the results obtained in the rodent model. It also makes it possible to scientifically validate the interest of β-cells produced in the laboratory as a genuine tool for exploring the mechanisms of diabetes. Finally, from a therapeutic perspective, it might be very interesting to develop a treatment that modulates the opening and closing of Ca2+ channels.

Ebola Virus: Detailed notice for the clinical trial being launched in Guinea

In Guinea, the epidemic caused by Ebola infection is still in the active phase nearly one year after it began. It is essential that measures for surveillance, control and management be accompanied by study of innovative therapies in order to reduce mortality. Potentially useful drugs include favipiravir (T-705), an antiviral drug already tested against influenza virus in adult humans (and well tolerated). The latter (no more than other potential treatments) has never been tested in humans for treating Ebola haemorrhagic fever, but its efficacy has been demonstrated in vitro and in mice.

The pilot clinical trial conducted by Inserm is aimed at testing the efficacy of favipiravir in reducing mortality in individuals infected by Ebola virus in Guinea. It began on tuesday 23rd december 2014 in Gueckedou.

  • What does this clinical trial involve?

The trial conducted by Inserm is a non-randomised open label multicentre Phase IIb trial All patients will receive the drug for 10 days. The drug favipiravir, which comes in the form of a 200 mg scored tablet (the tablet can be crushed and dissolved in a drink), will be administered according to the following dose regimen :

– Adults: D0: 2,400 mg at H0, 2,400 mg at H8 and 1,200 mg at H16, then 1,200 mg twice a day for 9 days;
– Children: doses adjusted to body weight.

Details of this dose regimen are the subject of a publication in the journal The Lancet Infectious Diseases.

  • For whom is it intended?

All patients entering these various centres at the time of the trial may take the drug favipiravir if they so wish. The main analysis of the trial will be focused on patients taking the treatment at disease onset (within 48 h of the start of symptoms), based on the hypothesis that the drug is most active when administered early. However, all patients capable of swallowing the drug will be offered the treatment, regardless of how long they have had symptoms when they arrive.

Before being enrolled in the trial, each participant will give his/her consent. Consent will indicate that they have fully understood the clinical protocol. The latter will be explained prior to consent, in the appropriate language, by professionals in psychosocial counselling.

Since the symptoms are somewhat non-specific (fever, diarrhoea, vomiting), the researchers will perform PCR (a test based on gene amplification), which must be positive for Ebola virus before the treatment is offered.

In order for the results to be interpretable, the researchers must enrol 60 people responding to these criteria, something that may result in their treating several hundred people in total, for all durations of symptoms combined. Interim analyses will be conducted on every 20th patient treated to “survey” the safety and efficacy of the treatment, and to decide on the relevance of continuing the trial in the exact same way, or with modifications.

        ●  Where will this trial take place?

The trial will take place in three Ebola Treatment Units (ETU) in Guinea:

Gueckedou (managed by MSF),
Macenta (managed by the French Red Cross),
Nzérékoré (managed by the Alliance for International Medical Action, ALIMA).

  • The team

The team conducting the clinical trial is based in Guekedou, in the Ebola Treatment Unit established by Doctors Without Borders/Médecins Sans Frontières (MSF). It should comprise some 30 individuals in total, including researchers, healthcare professionals and anthropologists. Coordination will be provided by French researchers from Inserm, and Guinean researchers from the Centre for Education and Research in Rural Health, under the authority of the National Ebola Response Coordination Committee in Guinea.

Relations with the community will be a central concern for the researchers, given the background of a serious epidemic and major health crisis, combined with a climate of justifiable distrust of outside interventions among the populations. A community committee to monitor the trial will be put in place before the trial is launched.

Coordinating investigators: Prof. Denis Malvy and Dr Sakoba Keita

Lead scientists: Dr Xavier Anglaret and Prof. France Mentré

        ●  Provisional schedule

Enrolment is planned between 15 December 2014 and 15 March 2015.

Duration of involvement by each participant: 30 days

Total expected duration of the protocol: 4 months

Total duration of the project: 8 months

The first results will be published in March 2015 at the earliest.

  • Funding

The European Commission is funding this trial for an amount of €700,000.

Frequently asked questions:

Why not administer the drug vs a placebo?

For a disease with a very high risk of mortality, the evidence that a treatment is effective can be deemed convincing on observing a lower mortality than expected, without recourse to a placebo-controlled comparative trial. The principles of the experimental design for this trial are those retained for all the other trials being arranged.

Can there be side-effects from the treatment, and how are they monitored?

Favipiravir has been well tolerated in trials where it was used against influenza. Since the dose employed against Ebola is higher, side-effects will, however, be closely monitored, although problems of toxicity are not generally expected.

And if the results are inconclusive?

Depending on the first interim results, the trial can be interrupted in order to move on to another drug, or continued, either on its own or in combination with other antiviral drugs or other interventions.

What are the terms of the contract with the Japanese company that sells favipiravir?

The terms of this contract are confidential, but Inserm’s private subsidiary, Inserm Transfert, will safeguard Inserm’s interests and those of the populations.

What ethical questions are being raised by this trial?

This trial is being conducted under particularly difficult conditions, but ethical considerations are making us face these conditions in order to make progress, rather than do nothing. Populations affected by Ebola, like any population, are entitled to have promising therapeutic avenues explored using rigorous methods.