Heatwave 2015: Be careful of the abnormally high death rate

From Tuesday 30th June, France will enter into an exceptional heatwave for this time of year.[1]. These remarkably high temperatures (around 40 °C) can have particularly harmful consequences on the health: tiredness, dehydration, heat stroke, respiratory, heart, metabolic problems, etc. If, for the most part, these inconveniences are minor, they are lethal in certain cases, particularly for the at-risk populations such as young children or the elderly.

France has already experienced an exceptional heatwave in 2003, responsible for a high death rate. The Inserm researchers at the Epidemiology Centre on the medical causes of death (CépiDc) have produced an estimate of the high death rate linked to this heatwave on a national and regional level.

The numbers from the study are available in the official report “Surmortalité liée à la canicule 2003 (High death rate linked to the 2003 heatwave

The official report prepared by the Inserm researchers in collaboration with the InVS from 2006 “Estimation de la surmortalité observée et attendue au cours de la vague de chaleur du mois de juillet 2006 (Estimation of the high death rate seen and predicted during the heatwave of July 2006)” is also available.

[1] France weather (Météo France) website « Vague de chaleur: vers des températures exceptionnelles pour un début juillet (Heatwave: exceptional temperatures for the start of July)»

Unable to cope with uncertainty: the gateway to psychosis?

Imagine being plunged into a world in which events did not always have the same consequences, and with rules that changed without your knowledge. How would you adapt? Uncertainty as a factor in decision making is a fundamental issue in general psychology. Our world turns out to be more or less predictable, and our brain has to adapt to this uncertainty to make the best possible choices in any situation. This is the subject that attracted Fabien Vinckier and Raphaël Gaillard, researchers at St Anne’s Hospital, Inserm and Paris Descartes University, in collaboration with Mathias Pessiglione, an Inserm researcher at the Brain and Spinal Cord Institute at Pitié–Salpêtrière Hospital, AP-HP, and Paul Fletcher, from the University of Cambridge in Great Britain. This study, which has been published in Molecular Psychiatry, reveals that our ability to adapt our decisions to the uncertainty inherent in any choice may be disrupted in the early stages of psychosis.

Participants were invited to play a computer game during which they had to decide whether to bet on symbols. The rules were not always applied, and were reversed from time to time (a symbol that always won money started to lose it, and vice versa). When subjected to these conditions, participants, in order to adapt their choices, had to be able to simultaneously detect changes in the rules of play and times of stability. It was possible to show, with the help of mathematical models, that to be most effective, participants use their confidence in the rules of play to make their choices.

In order to reproduce the conditions for the early stages of psychosis, participants were intravenously administered either a placebo or a very low dose of ketamine. Ketamine is an anaesthetic that is used daily in high doses in operating theatres, and which, at low doses, causes symptoms strongly resembling the early stages of a psychotic episode. Continuous measurement of the participants’ behaviour and brain activity using functional magnetic resonance imaging (fMRI) made it possible to identify the effects of ketamine.

Using this model, the researchers demonstrated that ketamine affects the ability of participants to distinguish times when the rules of play are stable, and optimise their behaviour accordingly.

Thus, they did not did not come to a point where they systematically bet on the winning symbol (i.e. betting 100% of the time, even though the symbol only actually won 80% of the time), as if a persistent doubt unsettled them. This impairment is correlated with a disturbance in the fronto-parietal brain network.

“This study characterises the key role of adaptation to uncertainty in decision-making, and its disruption in the early stages of psychosis. It should enable a better understanding of the onset of psychotic illness, and guide therapeutic innovation,” explains Raphaël Gaillard, Professor of Psychiatry at Paris Descartes University, and Head of the Department of Mental Health and Therapeutics at St Anne’s Hospital.

This study reveals, in a pharmacological model of psychosis, the disruption of a person’s ability to finely adapt his/her behaviour to the uncertain nature of the environment. The brain bases for this impairment have been identified (a fronto-parietal network), and can be linked to the molecular pathway on which ketamine acts, and which is currently the focus of a search for new treatments for schizophrenia.

These findings are a continuation of a publication that appeared in the journal Science (Whitson, Science, 2008) on the onset of apparently psychotic phenomena (superstitions, conspiracy theories) in people who are subjected to strong uncertainty. Some psychotic symptoms, such as the emergence of delusions, could be a type of inappropriate response to the inability to construct and maintain a stable representation of the worldPhotoCP web


Cases of tuberculosis in Limoges, what does this mean for vaccination?

While tuberculosis (BCG) vaccination is no longer mandatory in France, five new cases of tuberculosis were recorded in Limoges this week. This disease, far from having disappeared, causes 5,000 new cases of illness each year, and is responsible for 700 deaths. These latest cases have restarted the debate about vaccination:

Should we get vaccinated? Should we have our children vaccinated? How does a vaccine work? Does vaccination really protect us?

Against this background, Inserm researchers Annick Guimezanes and Marion Mathieu have replied as objectively as possible to the questions everyone wonders about in the 3rd popular science book in the Choc Santé collection: “Vaccination: Agression or Protection?”couverture2

In a clear and accessible style, drawing on the most recent advances in the area, it will enable everyone to better weigh the risks and benefits of vaccination.


The small intestine is involved in chronic inflammation in obese people

Obesity is caused by many complex factors, some of which are yet unknown. Researchers from the French National Centre for Scientific Research (CNRS), Inserm, Pierre and Marie Curie University (UPMC) and Paris Descartes University, in collaboration with clinician researchers from the Paris Public Hospitals (AP-HP), have just shown that severe obesity is accompanied by inflammation of the small intestine and a strengthening of the immune defences in that area. This phenomenon reduces enterocyte[1] sensitivity to insulin and increases nutrient absorption, thus exacerbating the disease. This work, carried out at the Cordelier Research Centre (Inserm/UPMC/Paris Descartes University) and the Institute of Cardiometabolism and Nutrition (ICAN – Inserm/UPMC/AP-HP), is published on 18 June in the journal Cell Metabolism.

Study of the mechanisms involved in human obesity is particularly interesting in the jejunum, a portion of the small intestine that plays a major role in the absorption of lipids and carbohydrates. Because of its location in the body, the jejunum is difficult to study, and its contribution to this metabolic disease was not well known. In this study, the researchers were able to obtain jejunum samples from patients during a surgical operation performed to reduce their obesity and associated diseases (gastric bypass). Samples from 185 individuals suffering from severe obesity were compared with jejunum samples from 33 non-obese individuals, who were operated on for other reasons.

The research teams, coordinated by Edith Brot-Laroche and Karine Clément, observed a state of chronic inflammation in the small intestine in these obese individuals, and colonisation of the jejunal epithelium by T lymphocytes, at a density that increased with degree of obesity. These immune system cells produce cytokines[2] that inhibit the insulin sensitivity of the absorbent cells of the intestinal epithelium. Since the action of insulin regulates nutrient absorption and blood sugar level, this immune system phenomenon thus contributes to the exacerbation of the patient’s clinical situation.


Diagram explaining the mechanisms associated with jejunal inflammation in obese people© Edith Brot-Laroche/Armelle Leturque/Sébastien André/Karine Clément

Additional clinical studies also showed that, in obese people, the increased density of T lymphocytes in the intestine is probably related to complications associated with obesity such as liver disease (NASH) and dyslipidaemia[3].

The results of this study have also shown that the projections of the intestinal mucosa in these patients, the villi, are longer than in non-obese subjects. This means that the small intestine’s surface area for exchange is increased by 250% (an increase in area equivalent to two tennis courts), and that the patients absorb more nutrients. This phenomenon, which is due to a reduction in apoptosis, a mechanism of cell death, also enhances the inflammatory action of the immune system in this region, exacerbating the disease.

Although insulin resistance in the adipose, hepatic, pancreatic and muscle tissue had already been observed in obese people, these studies highlight the existence of similar mechanisms in the small intestine, and offer opportunities for noninvasive therapeutic interventions to help reduce the inflammatory state of the intestine and combat obesity.

This project, which brought together two teams from IHU-ICAN, the teams led by Edith Brot-Laroche and Armelle Leturque at the Cordelier Research Centre and by Karine Clément at Pitié Salpêtrière Hospital, was supported by ANR-ALIA Nutra2sense, the MetaCardis European project, clinical research programes (AP-HP) and Investissements d’Avenir (ANR-IHU).

[1] Intestinal epithelial cells specialised in nutrient absorption.

[2] Molecules used in cellular communication.

[3] Dyslipidaemia is an abnormally high or low concentration of lipids (cholesterol, triglycerides, phospholipids or free fatty acids) in the bloodstream.

Autism: the value of an integrated approach to diagnosis

Researchers at Inserm (Inserm Unit 930 “Imaging and Brain”) attached to François-Rabelais University and Tours Regional University Hospital have combined three clinical, neurophysiological and genetic approaches in order to better understand the brain mechanisms that cause autism. When tested on two families, this strategy enabled the researchers to identify specific gene combinations in autistic patients that distinguished them from patients with intellectual disabilities.

This study, published in the journal Molecular Psychiatry, offers new prospects for the diagnosis and understanding of the physiological mechanisms of autism.

Autism is a condition characterised by great heterogeneity, both in terms of clinical manifestations and genetics. It is currently estimated that nearly 400 genes may be involved in this disorder. Diagnosis of this condition is all the more complex because it is often associated with other developmental disorders involving the same genes.

To improve diagnosis, the Inserm researchers used an original multimodal approach combining:

  • Clinical assessment
  • High-throughput genomic analysis to sequence all the genes
  • Analyses of the electrical activity of the brain in response to the perception of a change (electroencephalography – EEG)

Two families with members affected by autism and/or intellectual disability were given the benefit of this integrated approach. In these two families, all individuals affected by the condition carried a mutation in the NLGN4X gene, which manifested in the brain as problems in transmitting information by the neurons.

Using EEG, the researchers primarily observed an abnormal brain wave pattern, characteristic of patients with autism. The other family members, including those with intellectual disabilities, did not show this feature.

Thanks to this new approach, a second rare mutation was characterised and linked to atypical brain activity measured by EEG in autistic patients.

For Frédéric Laumonnier and Frédérique Bonnet-Brilhault, the main authors of this work, “This study helps us realise that there is no ‘gene for autism,’ but combinations of genes involved in neurodevelopment that affect the development of the neuronal networks targeted by this condition.”

Identifying these combinations is a key step in understanding the physiopathology, and ultimately in the development of targeted therapeutic drugs.

Autism is a pervasive developmental disorder that appears early in childhood and continues into adulthood. It presents as an altered ability to establish social interactions and communicate, and as behavioural problems. People with autism often seem imprisoned in a kind of inner world.

This work was supported by Fondation de France and the European Union (EU FP7 project Gencodys)

A new therapeutic approach for rare and serious kidney diseases

In an article published in the journal JASN on 22 May last, a team at the Paris Cardiovascular Research Centre (PARCC) (Paris Descartes University / Inserm / AP-HP) proposes a new approach for the treatment of serious kidney diseases. Under the leadership of Pierre-Louis Tharaux, this team focused on the ability of kidney cells to react to inflammation.

The kidney is an essential organ of the body. Its function is to filter the blood and eliminate wastes collected by the urine. This filtering function is mainly performed by specialised cells, the podocytes, located in structures known as glomeruli. In some people, an abnormal inflammatory process is triggered and results in lesions in the kidney and in these glomeruli, leading to serious kidney failure, constituting a genuine diagnostic and therapeutic emergency.

To date, the only treatment for these diseases, known as glomerulonephritis, involves targeting the immune system in order to reduce the inflammation causing this condition. Unfortunately, these therapies are only partly effective, and expose the patients being treated to a high risk of infection. For this reason, the team led by Pierre-Louis Tharaux at the Paris Cardiovascular Research Centre (PARCC) chose a different approach: they studied the possibility of stopping renal destruction by influencing the manner in which the kidney cells (the podocytes) react to inflammation.

In people without disease, a receptor known as PPARγ (peroxisome proliferator-activated receptor-gamma) is present in the kidney podocytes. While studying this molecule, the researchers discovered that it partly disappeared from the glomerular cells in a mouse model of the disease. Similarly, this reduction was also observed in the kidneys of affected patients, suggesting an important role for this receptor in the development of glomerulonephritis. To confirm their hypothesis, the scientists completely deleted PPARγ from the podocytes of mice. They then observed a clear aggravation in the severity of the kidney damage in these mice, thereby corroborating the requirement for PPARg to protect the kidney.

For therapeutic purposes, the team then had the idea of administering a PPARγ activator, pioglitazone, to these mice. Clinically developed to treat some kinds of type 2 diabetes, it was known for its beneficial anti-inflammatory effect. Surprisingly, its administration to mice, up to 4 days after onset of the disease, considerably reduced renal inflammation, and enabled the structure and function of the kidney to be maintained. This efficacy was lost when the PPARγ gene was absent from the podocytes, indicating that the core effect of the drug comes from its action on these cells rather than from a general anti-inflammatory effect, as had been thought.

“These results suggest a new indication for this class of drugs activating the PPARg pathway, which could turn out to be of benefit in cases of glomerulonephritis by preventing serious kidney failure, which still affects many patients,” says Pierre-Louis Tharaux.

binôme édition #6 at the Avignon Festival

The les sens des mots company, Inserm (French National Institute of Health and Medical Research) and ICM (Brain and Spinal Cord Institute) are pleased to invite you to a show presented during binôme édition #6 at the Avignon Festival:

Stimulation Cérébrale Profonde (Deep Brain Stimulation), by Camille Chamoux, author, following her meeting with Eric Burguière, a researcher in neurobiology with CNRS – INSERM – ICM.

Clotilde proudly introduces her new man, a researcher, to her entourage. But as Gérard, Clotilde’s father says, “a neurobiologist paid from our taxes to do experiments on mice—now that raises a good few questions.”

Monday 13 July 2015, 5:30-6:30 pm at Maison Jean Vilar (8 bis rue de Mons, 84000 Avignon)

In order to reach an increasingly wider audience, Inserm is creating new visions of science by uniting the world of research with that of arts and culture. It is in this context that Inserm has been a partner in binôme for the last 5 years.

binôme is a series of Theatre and Science shows based on scripts written by playwrights after interviewing researchers on film, inspired by an idea by Thibault Rossigneux, artistic director of the theatre company les sens des mots (the meaning of words).

Eric Burguière

The repetitive behaviours characteristic of a certain number of illnesses, particularly OCD (obsessive compulsive disorder), are central to Eric Burguière’s research. His Inserm team works to better understand the brain mechanisms that cause these behaviours, in order to better treat them.

Camille Chamoux

Camille Chamoux became known from her first one-woman-show, Camille Attaque, and her columns on Canal Plus television in l’Édition Spéciale or on Europe1 radio. She also co-wrote the film Les Gazelles (2013), directed by Mona Achache, and played the lead role in it. In 2014, she created her second show Née sous Giscard (Born under Giscard), which she published with Solitaires Intempestifs, at the Théâtre du Petit Saint-Martin, with stage direction by Marie Dompnier. She is currently writing a second feature-length film, acting in four films in 2015, and is preparing her next one-woman-show.

This show will be rerun three times in autumn:

– 25 September, at Théâtre de la Reine Blanche (Paris 18), programme in preparation

– 26 September, as part of the Curiositas festival in Gif sur Yvette, programme in preparation
– 7 October at 7 pm, at ICM (Paris 13) during Fête de la Science

Supported by SACD, CEA, CNRS, ICM, INERIS, INSERM, IRD, OSU Pythéas, PACA Region, DRRT and Culture Science PACA. In partnership with Maison Jean Vilar, Festival d’Avignon, Faïencerie–Théâtre de Creil, and proarti.

Restoring natural immunity against cancers

Scientists at the Institut Pasteur and Inserm have successfully increased the infiltration of immune cells into tumors, thus inducing the immune system to block tumor growth. In an article published in Nature Immunology, the scientists show that, in combination with existing immunotherapies, this process efficiently destroys cancer cells.

Chemokines are small molecules that can attract immune cells towards inflammatory tissues, acting for example during tumor development or upon infection, in order to support migration of lymphocytes into diseased tissues. However, these molecules may be degraded by enzymes, a process that limits the influx of immune cells. For example, the chemokine CXCL10, which induces the recruitment of T lymphocytes into pathological tissues, is rapidly degraded by the enzyme dipeptidylpeptidase 4 (DPP4).  

The Dendritic Cell Immunobiology Unit, led by Matthew Albert (Institut Pasteur and Inserm), had previously shown that increased levels of DPP4 and the degraded form of CXCL10 in hepatitis C patients correlate with patients’ inability to respond to interferon treatment. Following these results, the scientists predicted and have now confirmed that inhibiting this enzyme could improve the efficacy of immune responses, in particular antitumor responses.

In a recently published study, Rosa Barreira da Silva, Matthew Albert and their colleagues showed that oral administration of a specific DPP4 inhibitor (sitagliptin) slows the development of several types of cancer in mice. In addition, the authors demonstrated that DPP4 inhibition increased the infiltration of T lymphocytes into tumors, and that the combination of this innovative treatment with existing immunotherapies eradicated the tumor.  

DPP4 inhibition blocks tumor growth. Histological section of two mouse melanomas – (a) untreated and (b) treated with sitagliptin, a specific DPP4 inhibitor. Stain: hematoxylin and eosin; scale bar: 500 mm. © Institut Pasteur

Since health authorities have already approved DPP4 inhibitors for the treatment of type 2 diabetes, the conclusions drawn from these studies may quickly translate into clinical studies in humans. In fact, Matthew Albert’s team, in collaboration with clinical colleagues, has already submitted a proposal for a phase I clinical trial, to evaluate the impact of sitagliptin treatment in patients with hepatocellular carcinoma.   The cross-disciplinary nature of the projects undertaken by the teams at the Institut Pasteur and Inserm, along with collaboration between scientists and clinicians, allows clinical observations and scientific discoveries to be rapidly applied for the management of human disease.  

This project has received funding from the Pasteur-Roux grant, the French Cancer League (Ligue Contre le Cancer), the Fondation ARC cancer research organization and the French National Research Agency (ANR) as part of the “Immuno-Onco” LabEx (Laboratories of Excellence) program. 


Starting on Wednesday 17 June, nearly 700,000 candidates, from 13 to 93 years of age[1], will be taking the baccalauréat state examination.

These exam periods, often synonymous with stress and fatigue, are a tough ordeal for our mind and body. On the eve of the written examinations, your notification to attend, bag and piece of identification are all ready, but what about your memory? How do you boost it, and look after it? Is there still time to revise? Is there a specific diet that should be followed? How many hours’ sleep does the future graduate need to be in full possession of his/her faculties?

Joëlle Adrien, Inserm Research Director at Unit 1127, “Brain and Spinal Cord Institute (ICM)”, and Francis Eustache, Director of Inserm Unit – EPHE – UCBN 1077, “Neuropsychology and Functional Neuroanatomy of the Human Memory,” specialists in sleep and human memory, respectively, answer your questions.

[1] To find out more, visit the French National Ministry of Education website

Impact of environmental exposure to insecticides on the cognitive development of 6 year old children

In an article published in the journal Environment International, researchers from Inserm (Inserm Unit 1085 – IRSET, the Institute of Research in Environmental and Occupational Health, Rennes), in association with the Laboratory for Developmental and Educational Psychology, LPDE (Rennes 2 University), provide new evidence of neurotoxicity in humans from pyrethroid insecticides, which are found in a wide variety of products and uses. An increase in the urinary levels of two pyrethroid metabolites (3-PBA and cis-DBCA) in children is associated with a significant decrease in their cognitive performances[1], particularly verbal comprehension and working memory. This study was carried out on nearly 300 mother and child pairs from the PELAGIE cohort (Brittany).   

Pyrethroid exposure

Pyrethroids constitute a family of insecticides widely used in a variety of sectors: agriculture (various crops), veterinary (antiparasitics) and domestic (lice shampoo, mosquito products). Their mode of action involves blocking neurotransmission in insects, leading to paralysis. Because of their efficacy and relative safety for humans and mammals, they have replaced older compounds (organochorides, organophosphates, carbamate) considered more toxic.

Exposure of children to pyrethroids is common. It is different to adult exposure, due to the closer proximity of children to ground-level dust (which stores pollutants), more frequent hand-to-mouth contact, lice shampoos, etc. In children, pyrethroids are mainly absorbed via the digestive system, but are also absorbed through the skin. They are rapidly metabolised in the liver, and mainly eliminated in the urine as metabolites within 48 hours.

Given these elements and the mode of action (neurotoxicity) of pyrethroid insecticides, the researchers proposed the hypothesis of a possible effect of these contaminants on the nervous system and its development in children.

Contribution of the PELAGIE mother-child cohort

Pregnancy is also an important period of life for the future health of the child. For this reason, the researchers studied the PELAGIE mother-child cohort established between 2002 and 2006, which monitors 3,500 mother-child pairs. This cohort simultaneously considers exposure to pyrethroid insecticides during foetal life and childhood.

A total of 287 women, randomly selected from the PELAGIE cohort and contacted successfully on their child’s sixth birthday, agreed to participate in this study.

Two psychologists visited them at home. One assessed the child’s neurocognitive performances using the WISC scale (verbal comprehension index, VCI, and working memory index, WMI). The other psychologist characterised the family environment and stimuli that might have had a role on the child’s intellectual development, collected a urine sample from the child, and collected dust samples.

Exposure to pyrethroid insecticides was estimated by measuring levels of five metabolites (3-PBA, 4-F-3-PBA, cis-DCCA, trans-DCCA and cis-DBCA) in urine from the mother (collected between the 6th and 19th weeks of pregnancy) and from the child (collected on his/her 6th birthday).

A decrease observed in child cognitive performances

Results show that an increase in children’s urinary levels of two metabolites (3 PBA and cis-DBCA) was associated with a significant decrease in cognitive performances, whereas no association was observed for the other three metabolites (4-F-3-PBA, cis-DCCA and trans-DCCA). With respect to metabolite concentrations during pregnancy, there was no demonstrable association with neurocognitive scores.

“Although these observations must be reproduced in further studies in order to draw definite conclusions, they indicate the potential responsibility of low doses of deltamethrine in particular (since the metabolite cis-DBCA is its main metabolite, and selective for it), and pyrethroid insecticides in general (since the metabolite 3-BPA is a degradation product of some twenty of these insecticides),” explains Cécile Chevrier, Inserm Research Fellow, the main author of this work.

“The consequences of a cognitive deficit in children for their learning ability and social development constitute a handicap for the individual and for society. The research effort needs to be pursued in order to identify causes that could be targeted by preventive measures,” emphasises Jean-François Viel, a co-author of this work.

To find out more

The PELAGIE cohort

The PELAGIE study (Perturbateurs Endocriniens: Étude Longitudinale sur les Anomalies de la Grossesse, l’Infertilité et l’Enfance [Endocrine Disruptors: Longitudinal Study on Disorders of Pregnancy, Infertility and Children]) was established in response to concerns about health, particularly child health, due to the presence of toxic compounds in our daily environment. It has involved monitoring approximately 3,500 mother-child pairs in Brittany since 2002. An impact of antenatal exposure to contaminants (solvents and pesticides) on intrauterine development has been suggested; assessment of the consequences for child development is underway. The PELAGIE study is part of the European network of mother-child cohorts that constitute an epidemiological resource that is vast and complex, but indispensable for responding to these Public Health concerns.

[1] Cognitive functions are the brain’s abilities to communicate, observe the environment, concentrate, remember an event or accumulate knowledge.