Maternal mortality: a reduction in deaths from haemorrhage

The new report, “Maternal Mortality in France,” coordinated by Inserm Unit U953, Epidemiological Research Unit on Perinatal Health and Women’s and Children’s Health, announces a reduction in the rate of mortality due to postpartum haemorrhage—the leading cause of maternal mortality in France—for the 2007-2009 data compared to 2004-2006. Twenty recommendations have been formulated by the French National Expert Committee on Maternal Mortality[1] with the aim of raising awareness among health professionals and prospective parents, in consultation with the French National College of Obstetricians and Gynaecologists, the French Society of Anaesthetists/Obstetric Anaesthesia Club, and the French National College of Midwives. 

The epidemiological results of these studies are published in the November 2013 issue of Journal de Gynécologie Obstétrique et Biologie de la Reproduction.

Maternal death has become a very rare event, but remains a recognised and fundamental health indicator for a country, and a signal for health professionals and decision-makers of possible dysfunction in the care system. Maternal death is the death of a woman while pregnant or within 42 days, or one year, of termination of pregnancy, from any cause related to or aggravated by the pregnancy or its management but not from accidental or incidental causes.

From 2007 to 2009, 254 maternal deaths were identified, representing deaths of 85 women per year in France, from a cause related to pregnancy, childbirth or their aftermath, giving a maternal death rate of 10.3 per 100,000 live births.

France has a rate comparable to that of neighbouring European countries that have an enhanced surveillance system, and compares favourably to the Netherlands and the United States, where the rate is growing.

A new, encouraging finding is that maternal death from postpartum haemorrhage—the leading cause of maternal mortality in France—decreased during the 2007-2009 period compared with 2004-2006.

According to the improved methodology for measurement, which must be put on a permanent footing, the rate of maternal mortality is generally stable. It seems possible to reduce it even further, since progress has been made, i.e. a reduction in deaths associated with haemorrhage and a decrease in suboptimal care.

“These results need to be examined in the light of the substantial mobilisation in the last ten years of researchers and clinicians, whose attention was drawn to the initial results of this survey in order to evaluate and improve care in relation to obstetric haemorrhage. However, the improvement must be pursued, since approximately 50% of these deaths were considered “avoidable” in France under current conditions, and given the widespread access of pregnant women to antenatal surveillance and quality care,” comments Marie-Hélène Bouvier-Colle, Emeritus Research Director at Inserm Unit U953, Epidemiological Research Unit on Perinatal Health and Women’s and Children’s Health.

Maternal risk factors

Maternal age and nationality, and the region where death occurs are the main individual factors identified as being associated with maternal mortality.

Age is a key factor in maternal mortality: over 50% of deaths involve women aged between 30 and 39 years, which can be explained by the fact that pregnancy is generally occurring at an increasingly higher age, and by the distinctly elevated risk of maternal death after 35 years.

Significant differences are observed between nationalities: women of Subsaharan nationality have the highest maternal mortality rate, at 22.4 per 100,000, i.e. twice as high as that of French women.

Rates vary for the different regions in France—the rate of maternal mortality is higher than the national average in the overseas departments (32.2 per 100,000) and in Ile de France (12.5).

Other risk factors for maternal death are obesity and multiple pregnancies.

Obstetric causes of death

The leading direct causes of maternal mortality are obstetric haemorrhage, which represents 18% of deaths, and, something relatively new, pulmonary embolism (11%), and complications of hypertension (9%).

The big change concerns the percentage of postpartum haemorrhage, which has declined by half since the last report (8%, or 1.9/100,000, compared with 16%, or 2.5/100,000, in 2004-2006). This encouraging result is probably due to the mobilisation of professionals for the last few years.

Adequacy of care and avoidability

Care was judged “suboptimal,” i.e. non-compliant with current recommended practice and knowledge, for 60% of deaths reviewed, compared with 72% between 1990 and 2000, which represents a significant decrease. Deaths from haemorrhage show the largest proportion of suboptimal care (81%).

Maternal deaths were judged “avoidable” in 54% of cases, i.e. a modification in the patient’s care or attitude in terms of medical opinion could have changed the fatal outcome (error or delay in diagnosis, delay or inappropriate first aid, inadequate treatment, delay in treatment or in intervention, and neglect of the patient). This rate, stable over time, is still mainly due to inadequate or delayed treatment, which implies that there is room for improvement.

These results have enabled the authors of the report to make 20 recommendations, among which we can mention:

– the importance of involvement of care-givers in the reporting and review of maternal deaths, in order to ensure a better knowledge of the national profile of these cases.

– risk assessment prior to conception and at the start of pregnancy, through prevention: vaccination against influenza for women who are pregnant or may become pregnant, risk assessment for a pregnancy where there is a preexisting pathology,

– medical examination of the pregnant woman outside the obstetric arena (examination of the heart, for example),

– maintaining vigilance after delivery when the mother returns home, i.e. informing her of the signs of venous thromboembolic events and arterial ischaemic stroke. A measure the importance of which is emphasised by Gérard Lévy, President of the National Expert Committee, especially given that women are returning home sooner and sooner after delivery.

– the importance of post-mortem examinations in cases of maternal death,

– other messages concern the medical management of obstetric haemorrhage, infection, hypertensive diseases, amniotic embolism, and venous thromboembolism.


This new report analysed data from 2007 to 2009. The previous report, published in 2010, concerned data from 2001 to 2006.

At present, France has a specific methodology for identifying pregnancy-associated deaths based on several databases, namely those for: cause of death, the registry of births, and hospital inpatient visits.

The mission of the National Expert Committee on Maternal Mortality was to identify causes of maternal death through the detailed information compiled by the confidential survey conducted by the Inserm Unit 953 team, Epidemiological Research Unit on Perinatal Health and Women’s and Children’s Health. The present procedure was carried out in 3 stages:

– first, it was necessary to identify the chronological association of all deaths of women that occurred during pregnancy and up to one year after its end.

– next, a survey was carried out by volunteer clinicians, the assessors, on the medical team that monitored the pregnancy, attended at the birth and managed the complication.

– finally, the death was classified by the National Expert Committee who judged, in the light of the elements of the survey, whether there was a direct or indirect causal link between the death and the pregnancy, whether the care administered was optimal or suboptimal, and whether death was “unavoidable,” “possibly avoidable,” or “certainly avoidable,” given more adequate care or better observation of the patient.

[1]  The National Expert Committee (CNEMM) is made up of epidemiologists from Inserm Unit U953 and clinical experts listed on page 3 of the report.

Clinical trial launched to treat Sanfilippo B syndrome using gene therapy

A phase I/II gene therapy clinical trial for children suffering from Sanfilippo B syndrome, a rare genetic disease, enrolled a first patient in October of this year. The trial is being carried out and coordinated by the Institut Pasteur (the trial’s sponsor), Inserm, AFM-Téléthon and Vaincre les Maladies Lysosomales (VML). It is being conducted at Bicêtre Hospital (AP-HP) in Paris. If the treatment is successful it will pave the way towards the development of other gene therapy treatments using the same process.

Asthme enfant

© Inserm / Latron

Sanfilippo syndrome is a rare genetic disease (also referred to as an orphan disease) that affects approximately 1 in 100,000 children. It is caused by a gene mutation that affects lysosomes – organelles that play essential roles in cell functions – including digestion and protein recycling mechanisms. The first symptoms of the disease – hyperactivity, speech disorders – arise at roughly 2 years of age and lead to neurodegeneration, progressive hearing loss, gradual loss of autonomy and premature death, in most cases before the age of 20. There is currently no cure or treatments available to address either the symptoms or the progression of the disease.

This clinical trial is the result of 10 years of collaborative research* carried out by Professor Jean-Michel Heard and his team at the Institut Pasteur (Biotherapies for Neurodegenerative Diseases Unit, Institut Pasteur/Inserm U1115) in partnership with AFM-Téléthon and Vaincre les Maladies Lysosomales (VML). It is based on the development of a viral vector capable of delivering one of the four potentially mutated genes in Sanfilippo patients (corresponding to four essential lysosomal enzymes) to the patient’s brain cells. This trial focuses on the B form of the disease. Cells incorporate the missing gene, provided by the viral vector, into their DNA thus enabling them to produce the missing enzyme.

The treatment consists of several intracerebral vector deposits in several areas of the brain. It was administered to the first patient in October 2013 by Professors Marc Tardieu, from the pediatric neurology department at Bicêtre Hospital (AP-HP), and Michel Zerah, from the pediatric neurosurgery center at Necker Hospital (AP-HP). Scientists and medical professionals consider that the patient’s very young age – two and a half years old –increases the chances of the therapy’s success. Three other children will be enrolled into the trial over the coming months thanks to the cooperation and support of Vaincre les Maladies Lysosomales (VML).

The original construction of the viral vector, produced by the company uniQure, uses innovative technology which enables batches to be manufactured with a high level of purity. Because of this, the process is already compatible for large-scale use. uniQure was chosen as a partner  because it is the first company to receive market approval in Europe for a gene therapy treatment, Glybera®.

Due to the slow progression of Sanfilippo syndrome, benefits of the treatment on the natural progression of the disease will not be appreciated before several years. This trial, if successful, could also open the door to future applications of the viral vector in gene therapy treatments, particularly in the treatment of neurodegenerative diseases.

Mechanics and genetics: an indispensable cocktail for embryonic development

In the fruit fly Drosophila and zebrafish, mechanical strain may activate the genetic cascade that initiates the formation of the future organs during embryogenesis. A discovery made by Emmanuel Farge (Inserm Research Director at Institut Curie) and his staff might explain the emergence of the first complex organisms more than 570 million years ago.
The results of this work are published in the journal
Nature Communications.


signal de phosphorylation de la béta-caténine dans le tissu ventral qui invagine (mésoderme) dans l’embryon de Drosophile en vue ventrale  de haut © E Farge

Living things exist in a multiplicity of forms. At the very beginning—whether they are early multicellular or embryonic forms of life—they are all nothing more than a mass of cells. A long series of morphological changes causes all existing life forms to develop from this one form.

The embryo adopts a particular form at each stage of its development. These successive deformations, which are genetically regulated, in turn create mechanical strain within the embryo. This strain also seems to influence or even regulate the expression of genes involved in development.

From Drosophila to zebrafish

“Whether in zebrafish or Drosophila, we have found that activation of the β-catenin protein at the beginning of embryonic development follows mechanical compression developed during the very first change in the form of the embryo,” explains the researcher.

At the very start of development, a morphological change—known as invagination in Drosophila and epiboly in the zebrafish—allows expression of the genes that specify the mesoderm1[1], in response to the mechanical activation of β-catenin in tissues that are particularly deformed by these movements. Complex organs such as the muscles, heart, or gonads are derived from the mesoderm.

In their publication in Nature Communications, Emmanuel Farge and his team show in detail that the mechanical strain occurring during this morphological transition induces a modification of β-catenin (phosphorylation), which induces its relocation from the surface of the cell to its centre.

This protein may take on several roles: on the cell surface, it is responsible for cell-cell adhesion and may thus undergo mechanical strain, become phosphorylated and then released into the cell; within the cell, it can activate certain genes and thus modify the fate of the cells. Thus mechanical compression can lead to the acquisition of an identity similar to that of mesodermal cells following relocation of β-catenin to the interior of the cell. “To reproduce the mechanical strain naturally undergone by the embryo, we introduced liposome-encapsulated magnetic nanoparticles into the embryo, which we then exposed to a micromagnet.

An answer to the origins of evolution into complex organisms?

“The main point is that the mechanosensitivity of gene expression has been conserved by Drosophila and zebrafish during evolution,” explains the researcher. “Its origin therefore goes back to the last common ancestor shared by the two species, i.e. over 570 million years.” Moreover, specialists in evolution associate this same period with a major transition in evolution: the emergence of the mesoderm in ancestral life forms, possibly related to the jellyfish, for example, which do not have a mesoderm. The origin of this transition, which led to the development of complex organisms, such as the vertebrates, has not been well understood until now. Researchers are therefore only now on-track to answer this long-standing question.

Going back still further in time, mechanosensitivity might have even contributed to the emergence of the very first organisms. And what if compression, triggered, for example, in a mass of cells because it was resting on the substratum, gave rise to local deformation of the cell mass and thus activated the first invagination of the very first primitive gastric organ, as suggested by the experiments previously done by the team?

Cancer genes, reactivation of sensitivity to compression

Since the genes for embryonic development are implicated in the process of tumour progression, the mechanical induction of genes constitutes a new avenue for studying the development of cancers. The β-catenin protein is not unknown to cancer specialists. Thus during development of colon cancer, dysregulation of the β-catenin pathway is often described as one of the events correlated with loss of the APC gene. Furthermore, the development of cancer leads to the generation of physical strain affecting the neighbouring tissues.
It is a little as if the mechanism necessary for the development of the embryo were reawakened at the wrong moment. “Indeed”, underlines Emmanuel Farge, “when all is going well, APC protein degrades the β-catenin released into the cytoplasm by abnormal mechanical cues. When APC is mutated (which happens in 80% of colon cancers correlated with genome modifications), the β-catenin released into the cytoplasm is no longer degraded effectively, and is free to enter the nucleus and stimulate the expression of genes that promote tumour development.”


[1]  The mesoderm is one of the three embryonic germ layers, and is formed between the endoderm and ectoderm at the time of gastrulation. During development, it gives rise to most of the internal organs. Its existence is a feature of the most highly evolved organisms.

Stanislas Dehaene is awarded the Inserm Grand Prix for 2013

The annual Inserm awards ceremony will take place on Monday 2 December at the Collège de France. On this occasion, eight prizes will be awarded to women and men who contribute daily to the scientific excellence of the Institute.
Stanislas Dehaene will be awarded the Inserm Grand Prix for his body of work on consciousness, Ogobara Doumbo will receive the International Prize for his research on malaria, and Daniel Louvard will be awarded the Honorary Prize for his work on cancer.

Stanislas Dehaene, grand Prix Inserm 2013

Stanislas Deheane © P. Delapierre/Inserm

“I decided to become a researcher the day my father told me that the term was replacing that of inventor, a career fantasy that had always enthralled me. I was about ten years old, and I was a very handy young lad. I did woodwork, programming, and I took apart any appliances that came my way.”

Awareness of numbers and letters

What happens in the brain during a mathematical operation? How does reading or calculation mould our neuronal connections? Does the state of consciousness have a characteristic brain signature? Stanislas Dehaene is fascinated by such questions.

Today this neuroscientist, who started as a mathematician, is a professor of cognitive psychology at the Collège de France. He leads the Cognitive Neuroimaging Unit (Unit 992 Inserm/CEA, Paris-Sud University 11) at the NeuroSpin Centre, a large brain research facility in south Paris. In just a few years, he became a specialist in the brain architecture underlying cognitive functions. He also wants to understand “how education changes the brain, by language or reading, for example.”

Having worked extensively on numbers and letters, his team is now focusing on signatures of consciousness. “Our working hypothesis is that consciousness comes from a system of long-distance cortical connections that enables the brain to transmit information,” explains the researcher. “To be conscious is to have information available in the global neuronal workspace.” His staff have just identified a marker that enables patients in a vegetative state to be distinguished from those with minimal consciousness, a difficult distinction to make clinically. This distinction enables one to predict their likelihood of recovering brain activity.

At the same time, Stanislas Dehaene and his teams are involved in many cross-disciplinary studies. The latest is a huge collaborative project known as the Human Brain Project. “It involves inventing a machine that reproduces the properties of the human brain,” he outlines, “based on microchips designed to mimic the neurons.”

See Stanislas Dehaene’s complete profile in the latest issue of Science&Santé

Ogobara Doumbo, International Prize

Ogobara Doumbo, Prix International

Ogobara Doumbo © P. Fellous/Inserm

Brought up in the culture of traditional medicine practised by his ancestors in a Dogon village, Ogobara Doumbo was deeply affected by malaria, which was decimating the populations. Following a period working as a surgeon in the Mali bush villages, he decided to devote himself to biomedical research.

See Ogobara Doumbo’s complete profile in the latest issue of Science&Santé

Daniel Louvard, Honorary Prize

Daniel Louvard, prix honneur 2013

Daniel Louvard © P. Delapierre/Inserm

An accomplished physical chemist and biologist, Daniel Louvard is also a fine scientific strategist. He successfully reorganised the Institut Curie Research Centre, now internationally recognised for its work in cancer biology.

See Daniel Louvard’s complete profile in the latest issue of Science&Santé

And also:

Opecst-Inserm Award: Jacques Grassi

Research Awards: Dominique Costagliola and Gulnara Yusupova

Innovation Awards: Joseph Hemmerlé and Véronique Guyonnet-Dupérat

Chemotherapy: when our intestinal bacteria provide reinforcement

Research jointly conducted by investigators at Institut Gustave Roussy, Inserm, Institut Pasteur and INRA (French National Agronomic Research Institute) has led to a rather surprising discovery on the manner in which cancer chemotherapy treatments act more effectively with the help of the intestinal flora (also known as the intestinal microbiota). Indeed, the researchers have just shown that the efficacy of one of the molecules most often used in chemotherapy relies to an extent on its capacity to mobilise certain bacteria from the intestinal flora toward the bloodstream and lymph nodes. Once inside the lymph nodes, these bacteria stimulate fresh immune defences which then enhance the body’s ability to fight the malignant tumour.

Results of this work are published in the journal Science on 22 November 2013

bacteria - blue version


The intestinal microbiota is made up of 100,000 billion bacteria. It is a genuine organ, since the bacterial species that comprise it carry out functions crucial to our health, such as the elimination of substances that are foreign to the body (and potentially toxic), or keeping the pathogens that contaminate us at bay. They also ensure the degradation of ingested food, for better intestinal absorption and optimal metabolism. These millions of bacteria colonise the intestine from birth, and play a key role in the maturation of the immune defences.

However, the bacterial species that make up the intestinal microbiota vary from one individual to another, and the presence or absence of one or another bacterial species seems to influence the occurrence of some diseases, or, conversely, may protect us.

In the cancer area, the French team directed by Prof Laurence Zitvogel, Director of Inserm Unit 1015,Tumour Immunology and Immunotherapy,” at Institut Gustave Roussy, in close collaboration with Institut Pasteur (Dr Ivo Gomperts Boneca, “Biology and Genetics of the Bacterial Cell Wall” Unit) and researchers at INRA (Drs Patricia Lepage and Joël Doré, Micalis Unit, “Food Microbiology in the Service of Health”), has just provided evidence that the intestinal flora stimulates an individual’s immune responses to combat cancer during chemotherapy.

Cyclophosphamide is one of the most widely used drugs in chemotherapy. However, like any treatment, it involves side effects (inflammation of the mucosa etc.), and disrupts the normal balance of the intestinal microbiota. Certain bacteria (of the Gram+ group of bacteria) can pass the intestinal barrier and enter the bloodstream and lymph nodes.

These bacteria, once in the general circulation of the body, may be considered harmful, and the body generates an immune response.

“This chain reaction, a side effect of the treatment, actually turns out to be very useful,” explains Laurence Zitvogel. “Surprisingly, the immune response directed against these bacteria helps the patient to better fight his/her tumour, by stimulating fresh immune defence mechanisms.”

More specifically, immunisation against bacteria leads to the recruitment of effector lymphocytes different to those mobilised by chemotherapy. Their role consists of helping anti-tumour lymphocytes to stem the growth of tumours.

To verify these observations in mice, researchers suppressed all Gram+ bacteria from their intestinal microbiota. Results showed that the efficacy of the chemotherapy was reduced. The researchers also suggest that some antibiotics used during chemotherapy may destroy these Gram+ bacteria, and thus negate their beneficial effect.

“Now that these “beneficial” bacteria that potentiate the anti-tumour immune response have been identified, we should soon succeed in supplying more to the body, especially via pro- or prebiotics and/or a specific diet,” the researcher concludes.

This work has received support from the French National Cancer League, the French National Cancer Institute (lNCa; SIRIC SOCRATES) and from LABEX Onco-Immunology

Where and how are fear-related behaviours and anxiety disorders controlled?

A team of researchers at Inserm led by Cyril Herry (Inserm Unit 862, “Neurocentre Magendie,” Bordeaux) has just shown that interneurons located in the forebrain at the level of the prefrontal cortex are heavily involved in the control of fear responses. Using an approach combining in vivo recordings and optogenetic manipulations in mice, the researchers succeeded in showing that the inhibition of parvalbumin-expressing prefrontal interneurons triggers a chain reaction resulting in fear behaviour. Conversely, activation of these parvalbumin interneurons significantly reduces fear responses in rodents. 

This research is published in the journal Nature

Some traumatic events may lead to the development of severe medical conditions such as anxiety disorders or posttraumatic stress disorder (PTSD).

Anxiety disorders have a prevalence of approximately 18% worldwide.

Despite successful treatments, some patients relapse, and the original symptoms reappear over time (fear of crowds, recurring nightmares, etc.). An understanding of the neuronal structures and mechanisms involved in this spontaneous recovery of traumatic responses is essential.

All observations made by researchers indicate that fear behaviours are controlled in the forebrain at the level of the dorsomedial prefrontal cortex. This control of fear behaviour is based on the activation of neurons in the prefrontal cortex that are in contact with specific areas of the amygdala.

Using an innovative approach combining electrophysiological recording techniques, optogenetic manipulations and behavioural approaches, the researchers were able to demonstrate that fear expression is related to the inhibition of highly specific interneurons—the parvalbumin-expressing prefrontal interneurons.

More specifically, inhibition of their activity disinhibits the activity of the prefrontal projection neurons, and synchronises their action.

Synchronisation of the activity of different neuronal networks in the brain is a fundamental process in the transmission of detailed information and the triggering of appropriate behavioural responses. Although this synchronisation had been demonstrated as crucial to sensory, motor and cognitive processes, it had not yet been examined in relation to the circuits involved in controlling emotional behaviour.

“Our results identify two complementary neuronal mechanisms mediated by these specific interneurons, which accurately coordinate and increase the neuronal activity of prefrontal projection neurons, leading to fear expression,” explains Cyril Herry. 

The identification and better understanding of these neuronal circuits controlling fear behaviour should allow the development of new treatment strategies for conditions such as posttraumatic stress disorder and anxiety disorders. “We could, for example, imagine the development of individual markers for these specific neurons, or the use of transmagnetic stimulation approaches to act directly on excitatory or inhibitory cells and reverse the phenomena.”

How is fear analysed in an animal?

From an experimental standpoint, the classic Pavlovian conditioning procedure involves associating one stimulus, such as a sound, with another, unpleasant stimulus, such as a small electric shock. This first step allows the animal to establish a persistent aversive memory. In other words, the animal comes to remember and learn that the sound is associated with an unpleasant state, and an immobility response is routinely triggered, which is a good indication of fear in an animal.

In the second step, the extinction procedure involves repeated presentation of the sound alone, inducing a temporary inhibition of the conditioned fear responses. This inhibition is only temporary, as the mere passage of time favours the spontaneous recovery of the conditioned fear responses, which, from the clinical standpoint, may be associated with the phenomenon of relapse into traumatic responses seen following the treatment of posttraumatic stress disorder using exposure-based therapies.

Cancer treatment: a step towards personalized chronotherapy

Cancer chronotherapy consists in administering treatment at an optimal time. Because the body is governed by precise biological rhythms, the efficacy of anti-cancer drugs can be doubled and their toxicity reduced five-fold depending on the exact timing of their administration. However, important differences in biorhythms exist between individuals, which chronotherapy has not been able to take into account until now. An international study conducted on mice and coordinated by researchers from Inserm, CNRS and Université Paris-Sud[1] has paved the way towards personalized chronotherapy treatments. In an article published in the journal Cancer Research, the team has shown that the timing of optimal tolerance to irinotecan, a widely used anti-cancer drug, varies by 8 hours depending on the sex and genetic background of mice. They then developed a mathematical model that makes it possible to predict, for each animal, the optimal timing for administering the drug. They now hope to test this model on other drugs used in chemotherapy.

The body’s metabolism follows a 24 hour rhythm, driven by the circadian clock. Consequently, at certain precise times of the day or night, a given drug may prove to be more toxic to cancer cells and less aggressive to healthy cells. Cancer chronotherapy, discovered some twenty years ago by Francis Lévi, seeks to improve the efficacy of chemotherapy treatments. His research has shown that this efficacy can be doubled, depending on the time at which they are administered. Furthermore, it is precisely at this optimal time that the drugs prove to be five times less toxic to the body.

However, research points to the need for personalizing chronotherapy. Indeed, biorhythms can change from one person to the next. For example, although the optimal timing is the same for 50% of patients, the remaining 50% are either ahead of or behind this time. The team headed by Lévi wanted to elucidate the factors that affect these differences in biorhythms.

To do this, the researchers studied the toxicity of irinotecan, an anti-cancer drug widely used in the treatment of cancer of the colon and pancreas, as a function of the timing of its administration in four strains of male and female mice. For the first time, they were thus able to observe that the time of best tolerance to treatment varied by up to eight hours from one group of rodents to the next, depending on their sex and genetic background.

The researchers then worked on developing a method able to predict this optimal drug timing independently of sex and genetic background. To do this, they measured the expression of 27 genes in the liver and colon over 24 hours and then analyzed these measurements using a methodology derived from systems biology. In this way, the researchers were able to construct and validate a mathematical model to precisely predict the timing at which irinotecan is less toxic to the body using the expression curve of two genes, known as Rev-erbα and Bmal1, which regulate the metabolism and proliferation of cells.

The researchers are now aiming to validate this model on other drugs used in chemotherapy. In addition to gene expression, they would also like to find other physiological parameters related to the biological clock that could help predict the optimal timing of treatments for each patient. This work should make it possible to enhance the efficacy and tolerance of such treatments as well as considerably improve the quality of life of patients.

This project was funded in particular by the European Union (7th Framework Programme for Research and Technological Development) and ERASYSBIO+, the European consortium of funding bodies, ministries and project management agencies

[1] Coordinated by the Unité Rythmes Biologiques et Cancers (Inserm/Université Paris-Sud), this work also involved the Institut de Biologie de Valrose (CNRS/Inserm/Université de Nice Sophia Antipolis), the Laboratoire des Signaux et Systèmes (CNRS/Supélec/Université Paris-Sud) and the Milan Institute of Pharmacology.

Inserm and Fondation ARSEP organize the third meeting between researchers and patients

Multiple Sclerosis (MS) is a debilitating neurological disease which affects 80,000 individuals in France. At the moment, there is no known cause or cure. There are only treatments for the disease symptoms. Given the need to keep patients informed of progress in research, Inserm and Fondation ARSEP organise national meetings between researchers and patients every two years.

Last year the 2012 Researcher-Patient Meeting was, for researchers, clinicians and patients alike, an opportune moment for discussion and discovery.

For this 3rd meeting, to be held on Friday 22 November, 9 French research laboratories that have received support from Fondation ARSEP will be opening their doors to individuals with multiple sclerosis and their families. This unique national one-day meeting is based on dialogue and building a space where researchers and patients can share knowledge.

How can myelin be repaired and visualised? What modifications take place at the blood-brain barrier during the illness? What is the current status of viral research or antibody drugs? These are the types of questions that the researchers will try to answer.

List of research laboratories in France :

– Caen – Centre Cyceron
– Dijon – Centre d’investigation clinique/Faculté de médecine
– Grenoble – Institut Albert Bonniot – CHU
– Paris – ENS (Ecole Normale Supérieure) – Institut Cochin et l’ICM (Institut du Cerveau et de la Moelle Épinière)
– Strasbourg – Institut de physique biologique (l’Hôpital civil)
– Toulouse – Centre de Physiopathologie Toulouse-Purpan
– Marseille – Laboratoire CNRS universitaire et hospitalo-universitaire – CHU la Timone

Launch of third season of

Participation by members of the public in influenza surveillance via the Internet

Launched two years ago by the French GPs Sentinelles network (a joint research unit involving Inserm and the Université Pierre et Marie Curie) and the French Institute for Public Health Surveillance, the website is back for a third consecutive year. complements traditional surveillance systems for influenza, which are fed information collected in private physician practices and hospitals. These data facilitate research initiatives (at European as well as national level) aimed at gaining a better understanding of influenza—research on risk factors, the role of age, impact of vaccination, spread of the disease on a Europe-wide scale, etc.

The principle of the ( website is to allow anyone living in metropolitan France, whether ill or not, to participate in influenza surveillance anonymously and voluntarily if s/he wishes to do so.

Last year, had over 6,000 participants

Overview of the last season

During the last winter season, between 15 November 2012 and 21 April 2013, enabled the collection of a large quantity of influenza-related data. A little over 6,000 Internet users participated, and nearly 85,000 questionnaires were completed. All departments in metropolitan France were represented, and, as in the first season, women and individuals aged 60 to 69 years were the most frequent participants. The representativeness of participants in the study was the subject of a recent scientific publication (M. Debin et al. Evaluating the feasibility and participants’ representativeness of an online nationwide surveillance system for influenza in France. PLoS One. 2013 Sep 11;8(9):e73675).

Weekly collection of symptoms presented by participants allowed monitoring of the course of the influenza epidemic in the population. During the season, 29% of participants reported symptoms consistent with an influenza-like illness, compared with 23% during the first season. These figures may be explained by the fact that the 2012-2013 seasonal influenza epidemic was especially long, as shown by surveillance data from the Sentinelles network and the French Institute for Public Health Surveillance (InVS). The level of participants who consulted a physician for symptoms consistent with an influenza-like illness was 38% (These figures were similar to those seen during the first season). Of the regular participants in, 34% were vaccinated against seasonal influenza, compared with 20% of the general population.


Objectives for the new season, 2013-2014

Although the number of participants last year was very encouraging (and actually higher than observed for some other European countries that had launched their population-based influenza surveillance schemes before France), it remains insufficient to enable the course of the influenza epidemic to be studied in different population subgroups at present, especially in men and young participants.

In order for to provide the most reliable estimates possible, it is important for it to have the maximum number of participants, regardless of their state of health (low susceptibility to winter infections or often ill in winter), age, occupation, etc.


For this third season, several new elements can be noted:

  • Improvement in the “feedback” given to participants in their personal space

After completing the weekly questionnaires, participants will now have access to personalised feedback on their results, with new graphic and stylistic elements. This system will enable participants to compare their own results (level of participation, symptoms presented, etc.) with those of other participants (of the same age group or gender, for example).

  • Referral

Each participant may refer new participants via his/her account. All that is required is to complete the email address of individuals invited to participate in An email will be sent to them explaining the study and inviting them to participate.

  • Discover new features throughout the season…

New features introduced during the 2013-2014 season will help to make participation in more fun, in order to motivate more people to become involved in the project.

  • RSS feed available on the website, with maps and graphs from the study
  • New actions planned for Corsica (with the support of the Corsican Regional Authority)

Summary of the project

This surveillance system was launched at the end of January 2012 by the Sentinelles network (a joint research unit involving Inserm and the Université Pierre et Marie Curie) and the French Institute for Public Health Surveillance.

The system enables the collection of epidemiological data on influenza directly from members of the public in metropolitan France with the help of the Internet. Data compiled by are not intended to replace information validated by health professionals, but rather to provide additional information, especially on patients who do not consult health facilities.

Participation in, takes only a few minutes. When registering on the website, only an email address is required. After completing the questionnaire, the participant is invited each week to complete a short questionnaire summarising the symptoms experienced or not experienced since last logging in (fever, cough, etc.). These anonymous data are immediately analysed, and contribute in real time to influenza surveillance in France. Participation in this programme does not, of course, replace a visit to one’s GP. is a project funded by the French National Research Agency (ANR) under the HARMS-flu project (Harmonising Multiple Scales for Approaches to the Modelling of Influenza Spread in France). is part of a European population-based approach for the surveillance of influenza-like illness, Influenzanet. For this new season, 9 other European countries have adopted systems comparable to, and over 40,000 Europeans participated in this surveillance during the 2012-2013 season.

Identification of a new mechanism in the most commonly used immunotherapy for lymphoma

Using innovative dynamic imaging technique, scientists at the Institut Pasteur, Inserm and the VU Medical Center in Amsterdam have uncovered the mode of action of anti-CD20, an antibody therapy frequently used in the treatment of lymphomas (cancers of the immune system) as well as some auto-immune diseases. In a lymphoma model, the scientists have been able to carry out real time in vivo imaging of the cellular events activated by the treatment and resulting in the destruction of tumor cells. These discoveries should help optimize the efficacy of future therapies involving anti-CD20 antibodies. This work is the subject of an article published online November 1 on the Journal of Clinical Investigation website.

A lymphoma usually develops as a result of abnormal proliferation of one of two types of immune cells:  B lymphocytes (in the vast majority of cases) or T lymphocytes. For the last fifteen years or so, anti-CD20 antibody therapy has frequently been used in the treatment of B-cell lymphomas (in particular those known as non-Hodgkin lymphomas), in combination with conventional chemotherapy. These antibodies are directed against B lymphocytes, bind to cancer cells and mark them for depletion by other immune cells. Anti-CD20 antibody therapy also triggers a decrease in the normal B lymphocyte population, dampening immune responses. For this reason it is also used to treat autoimmune diseases. However, how anti-CD20 antibody therapy works in vivo was not fully understood.

A study led by Philippe Bousso, head of the Dynamics of Immune Responses Unit (Institut Pasteur / Inserm U668), along with researchers at Inserm and the VU Medical Center in Amsterdam, has provided the first conclusive answers. Using dynamic imaging techniques developed at the Institut Pasteur, the scientists have carried out real time in vivo imaging of the destruction of cancerous and normal B lymphocytes during anti-CD20 antibody treatment. The scientists noticed that the phenomenon of B lymphocyte depletion resulting from anti-CD20 antibody therapy primarily takes place in the liver and involves a specific cell type, known as Kupffer cells. The images produced by the scientists clearly show Kupffer cells (in green) capturing cancerous B lymphocytes (in orange) and preventing their circulation before destroying them.

These discoveries provide important insight for optimizing the efficacy of future treatments using anti-CD20 antibodies. Non-Hodgkin lymphomas affect 10,000 people per year in France, and account for 10% of pediatric cancers.